CN103570683B - Polysubstituted aminated compounds and its preparation method and application - Google Patents

Polysubstituted aminated compounds and its preparation method and application Download PDF

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CN103570683B
CN103570683B CN201210269204.6A CN201210269204A CN103570683B CN 103570683 B CN103570683 B CN 103570683B CN 201210269204 A CN201210269204 A CN 201210269204A CN 103570683 B CN103570683 B CN 103570683B
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methyl
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pyridine
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nmr
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CN103570683A (en
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龙亚秋
曹斌
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Shanghai Institute of Materia Medica of CAS
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/54—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/57—Nitriles
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
    • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
    • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
    • C07D235/06—Benzimidazoles; Hydrogenated benzimidazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
    • C07D235/14—Radicals substituted by nitrogen atoms
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

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Abstract

The invention belongs to pharmaceutical technology field, specifically, acceptable salt, ester, prodrug or hydrate on polysubstituted aminated compounds or its isomers or its pharmacy shown in the present invention provides the following general formula I, its pharmaceutical composition, its preparation method and its purposes in treatment AIDS-treating medicine is prepared.The compound or pharmaceutical composition comprising the compound can be used for the dimerization for suppressing protein protein interaction and hiv integrase between hiv integrase and LEDGF/p75 as inhibitor, and then available for treating AIDS.

Description

Polysubstituted aminated compounds and its preparation method and application
Technical field
The invention belongs to pharmaceutical technology field, and specifically, the present invention relates to polysubstituted aminated compounds or its isomers Or acceptable salt, ester, prodrug or hydrate in its pharmacy, its pharmaceutical composition, its preparation method are preparing treatment with it Purposes in AIDS-treating medicine.The compound or pharmaceutical composition comprising the compound can be used as inhibitor to be used to suppress HIV The dimerization of protein-protein interaction and hiv integrase between integrase and LEDGF/p75, and then can be used for treating AIDS Disease.
Background technology
Lens epithelium source property growth factor (lens epithelium derived growth factor, LEDGF) belongs to Liver cancer derivative growth factor (hepatoma-derived growth factor, HDGF) GAP-associated protein GAP (HRP) family, by it plus In the culture medium for entering crystalline epithelial cell, fibroblast, keratinocyte, cell growth can be promoted, extend cell survival (Poeschla E M.Integrase, LEDGF/p75and HIV replication.Cell Mol Life Sci, 2008, 65:1403-1424.).The LEDGF and transcription synergistic activation factor p75 having found is same albumen, because of referred to herein as LEDGF/ p75.But it is neither a kind of growth factor nor the albumen specifically expressed in crystalline epithelial cell, but is widely present in Albumen in the various cells of human body.LEDGF/p75 is when atopic dermatitis, asthma, interstitial cystitis occur when inflammation As a seed nucleus autoantigen, cause autoimmune response, induction of programmed cell is dead, with some autoimmune disease phases Close (Ganapathy V, Casiano C A.Autoimmunity to the nuclear autoantigen DFS70 (LEDGF):what exactly are the auto-antibodies trying to tell us?Arthritis Rheum,2004,50:684-688.).Early stage research also shows the interaction protein that LEDGF/p75 is transcriptional co-factor PC4 In vain, found that it can be by activating stress protein and Anti-apoptotic proteins, such as Heat shock protein 27/90, antioxidant protein 2 later Expression, protection cell is from the cell death (Shinohara T, Singh the D P, Fatma that are induced by pressure stressed condition N.LEDGF,a survival factor,activates stress-related genes.Prog Retin Eye Res, 2002,21:341-358.).Therefore, LEDGF/p75 plays important regulative to cell survival and apoptosis.
LEDGF/p75 is found in the nucleus extraction thing that co-immunoprecipitation is overexpressed integrase, causes people very big Concern.Further study show that LEDGF/p75 closes integrase chain onto DNA/ chromosomes, promote chain tra nsfer and integrate complete Into being the 1st cell helper factor being found in HIV-1 integration process.
LEDGF/p75 belongs to liver cancer derivative growth factor (HDGF) GAP-associated protein GAP (HRP) family, it has now been found that 6 HRP families Member：HDGF, HRP1, HRP2, HRP3, LEDGF/p75 and LEDGF/p52.On gene structure, HRP families N-terminal all contains 1 The C-terminal of a PWWP regions, wherein LEDGF/p75 and HRP2 have 1 evolution conservative sequence to be combined with HIV-1 integrases, claim For integrase binding domain (integrase-binding domain, IBD).LEDGF/p75 is made of 530 amino acid residues, 2 regions, N-terminal DNA/ chromosomes land and C-terminal integrase land can be divided into according to its function.
The transduction of the shRNA slow virus carriers of codified fluorescin and target practice LEDGF/p75 genes is entered into CD4+ cells, Strengthen RNA interference genes to suppress, make CD4+ cell infections HIV-1 it is horizontal decline 10~30 times (Llano M, Saenz D T, Meehan A,et al.An essential role for LEDGF/p75 in HIV integration.Science, 2006,314:461-464.)；In CD4+ cells be overexpressed green fluorescent protein-integrase binding domain (IBD) fusion protein with LEDGF/p75 competition binding integrases, make HIV-1 infection levels decline 7 times, and occur integrase CDD regions in passaged virus Tolerance strain (Hombrouck A, De Rijck J, Hendrix J, the et al.Virus evolution reveals of mutation An exclusive role for LEDGF/p75 in chromosomal tethering of HIV.PLoS Pathog, 2007,3:418-430.)；The integrase Q168 mutant strains that cannot be combined with LEDGF/p75 can not then be completed to replicate (Emiliani S,Mousnier A,Busschots K,et al.Integrase mutants defective for interaction with LEDGF/p75 are impaired in chromosome tethering and HIV-1 replication.J Biol Chem,2005,280:25517-25523.).These researchs fully demonstrate LEDGF/p75 and are Cell helper factor necessary to the duplication and infection of HIV-1.LEDGF/p75 plays a variety of effects in HIV integration process, at it Also there is similar (Busschots K, Vercammen J, Emiliani S, et al.The in his slow virus interaction of LEDGF/p75 with integrase is lentivirus-specific and promotes DNA binding.J Biol Chem,2005,280:17841-17847.).LEDGF/p75 albumen-integration enzyme interacting makes Integrase is from the ubiquitination (ubiquitination) of albumen and the degraded of vivo protein enzyme body.LEDGF/p75 is in integrase Nuclear translocation during also play certain effect.Importantly, LEDGF/p75 is beneficial to the phase interaction of integrase and nuclear chromatin With the progress of promotion viral integrase process.In testing in vitro, which not only excites the chain transfer activity of integrase, And the combination power of integrase and DNA can be made to improve more than 30 times of (Busschots K, Vercammen J, Emiliani S, et al.The interaction of LEDGF/p75 with integrase is lentivirus-specific and promotes DNA binding.J Biol Chem,2005,280:17841-17847.).So LEDGF/p75 is HIV-1 Cell helper factor necessary to duplication.
Then foreign protei can be degraded after entering cell immediately by ubiquitin tag by proteasome, and LEDGF/p75 can be with Integrase is combined and prevents from integrating enzyme hydrolysis, improves its stability (Llano M, Delgado S, Vanegas M, et al.LEDGF/p75 prevents proteasomal degradation of HIV-1 integrase.J Biol Chem, 2004,279:55570-55577.).The level of integrase mRNA is normal in the cell line of p75 defects, but can't detect integration Enzyme.Recover expression p75 in these cell lines, the cell concentration of integrase accordingly recovers normal, or is overexpressed green fluorescence The fusion protein of albumen-integrase binding domain (IBD) can also make integration enzyme level recover normal.
Bushman laboratories HIV integration sites substantial amounts of to human genome have carried out statistical analysis, it turns out that rich Active transcription unit (transcriptionunits, TUs) containing AT is that HIV-1 integrates preferential generation area, this and LEDGF/ The AT- hooks motif of p75 it is consistent to the special affinity of the DNA sequence dna rich in AT (ARW, Shinn P, Chen H, et al.HIV-1 integration in the human genome favors active genes and local hotspots.Cell,2002,110:521-529.).Generally believe that integrase is linked to specifically by some cell factors now On DNA integration sites, make viral DNA preferential incorporation to these specific sequences, cause the base for some integration high frequencies occurred Because of seat (locus).It is this by host determine the phenomenon of integration site in integrated mechanism it is common, for example, with retrovirus class As yeast transposon Ty3 by interacting with transcription factor TFIIIB or TFIIIC, and be incorporated into polymerase III and transcribe (Kirchner J, Connolly CM, Sandmeyer SB.Requirement of at one or two of nucleotide of beginning location proximate RNA-polymerase III transcription factors for in vitro positionspecific integration of a retrovirus-like element.Science,1995,267:1488-1491.), yeast turns Stand Ty5 by combined with Sir4p C-terminals part the heterochromatic dna that is incorporated into telomere or do not occur mating type change it is heavy Silent magazine sequence (Zhu Y, Dai J, Fuerst PG, et al.Controlling integration specificity of yeast retrotransposon.Proc Natl Acad Sci USA,2003,100:5891-5895.).With yeast swivel base The integrated mechanism of son is similar, and the lentiviridae that integrase can be combined with LEDGF/p75 shows height when integrating to TUs sequences Degree selectivity, such as human immunodeficiency virus (HIV), monkey immunodeficiency virus (SIV), feline immunodeficiency virus (FIV).And cannot The retrovirus combined with LEDGF/p75, as moloney murine leukemia virus (MLV) only has general selectivity to TUs sequences, And there is high selectivity to initiating sequence and CpG islands；MK virus (SFV) is also to initiating sequence and the CpG islands rich in GC (CpG island) has compared with high selectivity;Avian sarcoma leukemia virus (ASLV) is to integration site without special selectivity (Maele B,Busschots K,Vandekerckhove L,et al.Cellular co-factors of HIV-1 Integration.Trends Biochem Sci, 2006,31:98-105.Mitchell RS, Beitzel BF, Schroder ARW, et al.Retroviral DNA integration:ASLV, HIV and MLV show distinct target site preferences.PLoS Biol,2004,2:1127-1137.).In addition, knocking out LEDGF/p75 genes makes inhibition of HIV Integration is obstructed and influences to replicate, and remaining a small amount of integration is greatly reduced the selectivity of TUs, Er Dui CpG islands and initiating sequence Selectivity improve, this cannot be with reference to similar (Shun of selectivity of the retroviral integration site of LEDGF/p75 to other MC,Raghavendra NK,Vandegraaff N.LEDGF/p75 functions downstream from preintegration complex formation to effect gene-specific HIV-1 integration.Genes Dev,2007,21:1767-1778.Marshall HM,Ronen K,Berry C,et al.Role of PSIP1/LEDGF/p75 in lentiviral infectivity and integration targeting.PLoS One,2007,2:1-13.).It is special that a large number of experiments proves that integrase by LEDGF/p75 is linked to DNA Sequence (TUs) on integrated, result in the selectivity of HIV integration sequences, the research of this respect is closed mechanism for its chain and provided Strong evidence.
The integrase of HIV can be catalyzed 3' processing and two processes of chain tra nsfer, and the dimer of integrase is by HIV-1 cDNA's 13 '-GT dinucleotides is removed in U3, U5 end respectively, forms the stagger that can be matched with chromosomal DNA.Then connect Two integrase dimer oligomerisationizations at cDNA both ends form the integrase tetramer, and correlated virus and host factor, which enter, to be formed Compound (pre-integration complex, PIC) before integration, which occurs in endochylema.Compound enters before integration Nucleus, and complete chain tra nsfer under the catalysis of integrase.In vivo, the dimer of integrase can be by the one of HIV-1 cDNA End is incorporated into host DNA, is known as half and integrates (half-site integration)；And the integrase tetramer can be by HIV-1cDNA Both ends be all incorporated into host DNA, be known as complete integrating (full-site integration).Raghavendra is observed LEDGF/p75 promotes the half of HIV cDNA to integrate and suppress complete and integrate, and by experiment demonstrate LEDGF/p75 may interfere with it is whole The multimerization of synthase, but do not influence the catalytic activity of compound before integrating.Therefore speculate, LEDGF/p75 is in the integrase tetramer Play a role after being formed with compound before integration, support LEDGF/p75 and be attached on DNA/ chromosomes as a kind of conjunction of chain Viewpoint (Raghavendra NK, the Engelman A.LEDGF/p75 interferes with the formation of the factor of synaptic nucleoprotein complexes that catalyze full-site HIV-1 DNA integration in vitro:implications for the mechanism of viral cDNA integration.Virology,2007,360:1-5.)。
The AntiHIV1 RT activity infection medicine that highly active antiretroviral therapy uses at present is mainly protease inhibitors and reverse transcription Enzyme inhibitor, this two classes medicine easily produce drug resistance and toxicity, find novel mechanism and are not likely to produce the medicine of drug resistance It is the top priority of current anti-AIDS drug research.LEDGF/p75 is combined with HIV-1 integrases in vivo, is its integration Cell helper factor necessary to process, duplication and infection to HIV play an important role, therefore LEDGF/p75 is in anti-hiv therapy plan Become the promising target of drug research in slightly.
So the protein-protein interaction between hiv integrase and LEDGF/p75 and HIV integration can be suppressed by developing The dimerization of enzyme simultaneously there is treatment of the inhibitor of potential drug purposes to AIDS to seem particularly significant.
The content of the invention
Goal of the invention
The object of the present invention is to provide acceptable in a kind of polysubstituted aminated compounds or its isomers or its pharmacy Salt, ester, prodrug or hydrate, it can be whole as the protein-protein interaction between hiv integrase and LEDGF/p75 and HIV The inhibitor of synthase dimerisation.
It is a further object to provide the preparation method of the compound of the present invention.
The a further object of the present invention is to provide polysubstituted aminated compounds or its isomers provided by the invention or its medicament On acceptable salt, ester, prodrug or hydrate as the protein-protein interaction between hiv integrase and LEDGF/p75 and The application of the inhibitor of hiv integrase dimerization, and preparing the application in treating AIDS-treating medicine.
A further object of the present invention is to provide a kind of one or more provided by the inventionization for including therapeutically effective amount Compound or its pharmaceutically acceptable salt, ester, the pharmaceutical composition of prodrug or hydrate.
It is also another object of the present invention to provide a kind of method for treating AIDS.
Technical solution
To achieve these goals, the present invention provides the polysubstituted aminated compounds or its pharmacy shown in a kind of general formula I Upper acceptable salt, ester, prodrug or hydrate,
Wherein,
R1For C that is unsubstituted or being substituted by 1-3 substituent5-C12Aryl or 5 to 12 unit's heteroaryls, described 5 arrive 12 unit's heteroaryls contain the 1-2 hetero atom in N, O and S, the C5-C12Aryl or 5 to 12 unit's heteroaryls are preferably One of following groups：
5 to 12 unit's heteroaryls are more preferably one of following groups：
The wherein described substituent is selected from following atom or group：C1-C6Alkyl, C2-C6Alkenyl, C1-C6Alkoxy, C1-C6Alkylamino radical, C3-C8Cycloalkyl, halogen, amino, hydroxyl, morpholinyl, cyano group C1-C6Alkylidene, cyano group C1-C6Alkenylene, CN、CF3、NO2, it is unsubstituted or by selected from C1-C6Alkyl, C1-C6Alkoxy, halogen, amino, NO2, sulfydryl, hydroxyl, CN and CF3 In the C that is substituted of 1-3 substituent5-C12Aryl, containing the 1-2 in N, O and S it is heteroatomic unsubstituted or by Selected from C1-C6Alkyl, C1-C6Alkoxy, halogen, amino, NO2, sulfydryl, hydroxyl, CN and CF3In 1-3 substituent substituted 5 to 12 unit's heteroaryls ,-(CH2)o-C(O)-OH、-(CH2)o-C(O)-OR7、-(CH2)o-C(O)-NR5R6、-(CH2)o- NR7R8、-(CH2)o-NHC(O)R9With-(CH2)o-NHS(O)2R10, wherein o be 1-6 integer, R5And R6Can be mutually the same or not Together, hydrogen, C are each independently and1-C6Alkyl, C3- C8 cycloalkyl is unsubstituted or by selected from C1-C6Alkyl, halogen, Amino, NO2, sulfydryl, hydroxyl, CN and CF3In the benzyl that is substituted of 1-3 substituent, R7And R8It can be same to each other or different to each other, And it is each independently hydrogen or C1-C6Alkyl, R9For C1-C6It is alkyl, unsubstituted or by selected from C1-C6Alkyl, halogen, ammonia Base, NO2, sulfydryl, hydroxyl, CN and CF3In 1-3 the substituent benzyl, the C that are substituted1-C6Alkoxy carbonyl or C1-C6Alkanamine Base carbonyl, R10For C1-C6Alkyl；
R2For 5 to 12 membered nitrogen-containing heteroaryl bases that are unsubstituted or being substituted by 1-3 substituent, described 5 to 12 yuan contain Azepine aryl is preferably one of following groups：
The wherein described substituent is selected from following atom or group：C1-C6Alkylamino radical, halogen, amino, hydroxyl, CF3、CN、 NO2, it is unsubstituted or by selected from C1-C6Alkyl, halogen, amino, NO2, sulfydryl, hydroxyl, CN and CF3In 1-3 substituent institute Substituted benzyl, C1-C6Alkoxy carbonyl, C1-C6Alkylaminocarbonyl, morpholinyl, piperazinyl, N-C1-C6Alkylpiperazinyl, cyano group C1-C6Alkylidene and-(CH2)o- C (O)-OH, wherein o are the integer of 1-6；
R3For hydrogen, C1-C6Alkyl, it is unsubstituted or on pyridine ring by 1-3 C1-C6The pyridine radicals methylene that alkyl is substituted Base or-(CH2)o-NR11R12, wherein o be 1-6 integer, R11And R12It can be same to each other or different to each other, and be each independently hydrogen Or C1-C6Alkyl；And
R4For hydrogen or and R1And adjacent carbon atom forms 5 to 12 circle heterocycles bases, R together4With R1And adjacent carbon is former Son is preferably formed as one of following groups together：
In above-mentioned general formula I, R1To be unsubstituted or substituted by 1-2 substituentAnd R4For hydrogen, i.e., Compound shown in general formula I is preferably the compound shown in the following general formula II：
Wherein,
K1And K2It can be same to each other or different to each other, and be each independently selected from following atom or group：Hydrogen, C1-C6Alkyl, C2-C6Alkenyl, C1-C6Alkoxy, C1-C6Alkylamino radical, C3-C8Cycloalkyl, halogen, amino, hydroxyl, morpholinyl, cyano group C1-C6 Alkylidene, cyano group C1-C6Alkenylene, CN, CF3、NO2, it is unsubstituted or by selected from C1-C6Alkyl, C1-C6Alkoxy, halogen, ammonia Base, NO2, sulfydryl, hydroxyl, CN and CF3In the C that is substituted of 1-3 substituent5-C12Aryl, contain the 1-2 in N, O and S It is a heteroatomic unsubstituted or by selected from C1-C6Alkyl, C1-C6Alkoxy, halogen, amino, NO2, sulfydryl, hydroxyl, CN and CF3 In 1-3 substituent substituted 5 to 12 unit's heteroaryls ,-(CH2)o-C(O)-OH、-(CH2)o-C(O)-OR7、-(CH2)o-C (O)-NR5R6、-(CH2)o-NR7R8、-(CH2)o-NHC(O)R9With-(CH2)o-NHS(O)2R10, wherein o be 1-6 integer, R5With R6It can be same to each other or different to each other, and be each independently hydrogen, C1-C6Alkyl, C3-C8Cycloalkyl or it is unsubstituted or by selected from C1-C6Alkyl, halogen, amino, NO2, sulfydryl, hydroxyl, CN and CF3In the benzyl that is substituted of 1-3 substituent, R7And R8But that This is identical or different, and is each independently hydrogen or C1-C6Alkyl, R9For C1-C6It is alkyl, unsubstituted or by selected from C1-C6 Alkyl, halogen, amino, NO2, sulfydryl, hydroxyl, CN and CF3In 1-3 the substituent benzyl, the C that are substituted1-C6Alkoxy carbonyl Base or C1-C6Alkylaminocarbonyl, R10For C1-C6Alkyl,
K1And K2Independently of one another be preferably hydrogen, methyl, ethyl, isopropyl, vinyl, methoxyl group, cyclopropyl, F, Cl, Br、CN、NO2, amino, hydroxyl, phenyl, 3,5-dimethylphenyl, methoxyphenyl, (trifluoromethyl) phenyl, morpholinyl, indyl ,- (CH2)2-CN、-(CH)2-CN、-(CH2)2-COOCH3、-(CH2)2-COOH、-(CH2)2-C(O)-NH2、- (CH2)2-C(O)-N(CH3)2、-(CH2)3-N(CH3)2、-(CH2)3-NHC(O)CH3、-(CH2)3-NHS(O)2-CH3、-(CH2)3-NH2OrAnd particularly preferably K2For hydrogen, and K1On 3 on pyridine ring；
R2For one of following nitrogenous heteroaryl that is unsubstituted or being substituted by 1 substituent：
R2One of preferably unsubstituted or following nitrogenous heteroaryl for being substituted by 1 substituent：
R2One of more preferably unsubstituted or following nitrogenous heteroaryl for being substituted by 1 substituent：
The definition of the wherein described substituent is the same as R in general formula I2On substituent definition,
The substituent is preferably tert-butoxycarbonyl (boc) ,-COOMe ,-(CH2)2- CN, benzyl or 4- methyl piperazines Base；And
R3For hydrogen, C1-C6Alkyl, it is unsubstituted or on pyridine ring by 1-3 C1-C6The pyridine radicals methylene that alkyl is substituted Base or-(CH2)o-NR11R12, it is preferably hydrogen, methyl ,-(CH2)4-NH2Or 3- picolyls.
In above-mentioned general formula II, K2For hydrogen, K1On 3 on pyridine ring, R2For it is unsubstituted or by 1 substitution Base substitutionSubstituent thereon is positioned at 1 upper (K4), and R3For methyl, i.e. chemical combination shown in general formula II Thing is preferably the compound shown in the following general formula II-a：
Wherein K1Definition with its definition in general formula II；And K4Selected from following atom or group：Hydrogen, C1-C6Alkanamine Base, halogen, amino, hydroxyl, CF3、CN、NO2, it is unsubstituted or by selected from C1-C6Alkyl, halogen, amino, NO2, sulfydryl, hydroxyl, CN and CF3In 1-3 the substituent benzyl, the C that are substituted1-C6Alkoxy carbonyl, C1-C6Alkylaminocarbonyl, morpholinyl, piperazine Base, N-C1-C6Alkylpiperazinyl and cyano group C1-C6Alkylidene, is preferably hydrogen, boc ,-(CH2)2- CN ,-COOMe or benzyl.
Compound shown in above-mentioned general formula II-a is more preferably the compound shown in the following general formula II-a1 to II-a5：
Wherein K1Definition with its definition in general formula II-a.
In above-mentioned general formula II, K1On 3 on pyridine ring, K2For on 5 on pyridine ring, R2Not take It is generation or being substituted by 1 substituentSubstituent thereon is positioned at 7 upper (K5), i.e., shown in general formula II Compound is preferably the compound shown in the following general formula II-h：
Wherein K1、K2And R3Definition with its definition in general formula II；And K5Selected from following atom or group：Hydrogen, C1- C6Alkylamino radical, halogen, amino, hydroxyl, CF3、CN、NO2, it is unsubstituted or by selected from C1-C6Alkyl, halogen, amino, NO2, mercapto Base, hydroxyl, CN and CF3In 1-3 the substituent benzyl, the C that are substituted1-C6Alkoxy carbonyl, C1-C6Alkylaminocarbonyl, morpholine Base, piperazinyl, N-C1-C6Alkylpiperazinyl, cyano group C1-C6Alkylidene and-(CH2)o- C (O)-OH, wherein o are the integer of 1-6, Preferably hydrogen or 4- methyl piperazine bases.
Compound shown in above-mentioned general formula II-h is more preferably the compound shown in the following general formula II-h1 to II-h6：
Wherein K1And K2Definition with its definition in general formula II-h.
In above-mentioned general formula I, R1ForR3For methyl, and R4For hydrogen, i.e. chemical combination shown in general formula I Thing is preferably the compound shown in the following general formula III：
Wherein R2Definition with its definition in general formula II, and R2It is particularly preferably unsubstituted or by 1 substitution
One of following nitrogenous heteroaryl of base substitution：
In above-mentioned general formula I, R1ForR3For-(CH2)4-NH2, and R4For hydrogen, i.e., shown in general formula I Compound is preferably the compound shown in the following general formula IV：
Wherein K1、K2And K3It can be same to each other or different to each other, it is defined independently of one another with R in general formula I1On substituent Definition, independently of one another preferably hydrogen, methyl, ethyl, isopropyl, vinyl, methoxyl group, cyclopropyl, F, Cl, Br, CN, NO2、 Amino or hydroxyl.
In above-mentioned general formula I, R4With R1And adjacent carbon atom forms one of following groups together：Compound i.e. shown in general formula I is preferably the compound shown in the following general formula V or VI：
Wherein R2And R3Definition with its definition in general formula II, R2Particularly preferablyOrWherein K4Definition with its definition in general formula II-a, particularly preferably hydrogen or boc, and R3It is special You Xuanwei not methyl or-(CH2)4-NH2。
In the present invention, particularly preferred particular compound is following compounds：
Another aspect of the present invention provides a kind of preparation method of the polysubstituted aminated compounds shown in general formula I, should Method can be realized by formulas below：
Wherein, R1、R2、R3And R4Definition with the definition in general formula I, X is halogen,
And this method comprises the following steps：
Step 1)：Make compound II and R3-NH2Carry out reduction amination and obtain compound III, such as first room in methyl alcohol Temperature stirring 0.5 it is small when after add sodium borohydride be stirred for 2 it is small when；
Step 2)：Make compound III and compound IV --- R2- CHO carries out reduction amination, or makes compound III and compound IV --- R2-CH2- X carries out nucleophilic substitution, obtains compound I, such as first to compound III and R2-CHO Middle addition sodium triacetoxy borohydride, and be stirred overnight at room temperature in 1,2- dichloroethanes, or make compound III and R2- CH2- X carried out in potassium iodide, N, N- diisopropylethylamine and acetonitrile back flow reaction 7 it is small when.
Specifically, above-mentioned preparation method can be realized by the method shown in formulas below：
Wherein, R2And R3Definition with the definition in general formula I, X is halogen, and G is any group,
And this method comprises the following steps：
Step a)：Make 3- bromine-2-methylpyridines carry out heck with acrylonitrile to react to obtain compound A, usable palladium, Tetrabutylammonium chloride, sodium acid carbonate, n,N-Dimethylformamide make solvent, react 5h at 110 DEG C under blanket of nitrogen；
Step b)：Compound A catalytic hydrogenations are made to obtain compound B, usable palladium carbon makees catalyst, methanol as solvent, room Temperature reaction is overnight；
Step c)：Compound C is obtained with hydrogen peroxide oxidized compound B, usable acetic acid is made solvent, stirred at 80 DEG C anti- Answer 5.5h；
Step d)：Compound D is obtained with acetic anhydride process compound C, acetic anhydride can be used directly to make solvent, at 115 DEG C Stirring reaction 4h；
Step e)：Compound D is set to be hydrolyzed to obtain compound E with alkali, usable sodium methoxide makees alkali, methanol as solvent, It is stirred at room temperature；
Step f)：Oxidized compound E obtains compound F, and Dai Si-Martin's oxidant can be used, and dichloromethane makees solvent；
Step g)：Reduction amination compound F obtains compound G, and usable sodium triacetoxy borohydride makees reduction amination Reagent, 1,2- methylene chloride as solvent, is stirred overnight at room temperature；
Step h)：Make compound G and R2- CHO carries out reduction amination, or makes compound G and R2-CH2- X carries out parent Core substitution reaction, obtains compound H, and sodium triacetoxy borohydride can be used to make reduction amination reagent for reduction amination, and 1, 2- methylene chloride as solvent, is stirred overnight at room temperature, and nucleophilic substitution can make compound G and R2-CH2- X is in potassium iodide, N, N- bis- When back flow reaction 7 is small in wopropyl ethyl amine and acetonitrile；
Step i)：The cyan-hydrolysis in compound H is obtained carboxylic acid compound I, usable sodium hydroxide makees alkali, ethanol and Water makees mixed solvent, be refluxed 10 it is small when；
Step j)：Make compound I carry out being condensed to yield compound J from different amine, benzotriazole-N, N can be used, N', N'- tetramethylurea hexafluorophosphoric acid ester make condensing agent, and n,N-diisopropylethylamine makees alkali, and n,N-Dimethylformamide makees solvent, 12h is stirred at room temperature in mixture；
Step k)：The cyan-hydrolysis in compound H is obtained ester K, reagent and solvent can be made using concentrated hydrochloric acid, reflux is stirred Mix 12 it is small when, add methanol afterwards, then be refluxed 2 it is small when.
An additional aspect of the present invention provides the preparation method of the polysubstituted aminated compounds shown in another general formula I, This method can be realized by formulas below：
Wherein, R1、R2、R3And R4Definition with the definition in general formula I, X is halogen,
And this method comprises the following steps：
Step a)：Make compound IV --- R2- CHO and R3-NH2Reduction amination is carried out, or makes R3-NH2With chemical combination Thing IV --- R2-CH2- X carries out nucleophilic substitution, obtains compound VI, such as first to R3-NH2And R2Triacetyl is added in-CHO Epoxide sodium borohydride, and be stirred overnight at room temperature in 1,2- dichloroethanes, or make R3-NH2With R2-CH2- X in potassium iodide, N, When progress back flow reaction 7 is small in N- diisopropylethylamine and acetonitrile；
Step b)：Compound VI and compound II is carried out reduction amination and obtain compound I, such as first to compound VI With sodium triacetoxy borohydride is added in II, and be stirred overnight at room temperature in 1,2- dichloroethanes.
Specifically, above-mentioned preparation method can be realized by the method shown in formulas below 1-3：
Reaction equation 1：
Wherein, R2And R3Definition with the definition in general formula I, X is halogen, K6For C1-C6Alkyl,
And this method comprises the following steps：
Step a1)：Make compound IV --- R2- CHO and R3-NH2Reduction amination is carried out, or makes R3-NH2With chemical combination Thing IV --- R2-CH2- X carries out nucleophilic substitution, obtains compound VI, such as first to R3-NH2And R2Triacetyl is added in-CHO Epoxide sodium borohydride, and be stirred overnight at room temperature in 1,2- dichloroethanes, or make R3-NH2With R2-CH2- X in potassium iodide, N, When progress back flow reaction 7 is small in N- diisopropylethylamine and acetonitrile；
Step b1)：Compound E catalytic hydrogenations are made to obtain compound L, usable Raney's nickel makees catalyst, saturated ammonia methanol Make solvent, room temperature reaction is overnight；
Step c1)：Compound L reduction amination is set to obtain compound M, usable alkyl aldehydes make reagent, and ethanol-acetic acid mixes Bonding solvent, palladium carbon make catalyst, 9h are stirred at room temperature under a hydrogen atmosphere；
Step d1)：Oxidized compound M obtains compound N, and usable dichloromethane makees solvent, and Dai Si-Martin's oxidant is made Oxidant, is stirred at room temperature reaction overnight；
Step e1)：Compound N is carried out reduction amination with compound VI and obtain compound O, such as first to compound VI With adding sodium triacetoxy borohydride in N, and it is stirred overnight at room temperature in 1,2- dichloroethanes.
Reaction equation 2：
Wherein, R2And R3Definition with the definition in general formula I, X is halogen, and G is any group,
And this method comprises the following steps：
Step a2)：With the step a1 in reaction equation 1)；
Step b2)：With the step b1 in reaction equation 1)；
Step c2)：Compound L is carried out amidation process from different acyl chlorides, acid anhydrides or carboxylic acid, obtain compound P, such as Acid anhydrides and triethylamine are first added into compound L, then is stirred overnight at room temperature in methyl alcohol；Or into compound L add carboxylic acid, Benzotriazole-N, N, N', N'- tetramethylurea hexafluorophosphoric acid ester and n,N-diisopropylethylamine, then in N, N- dimethyl formyls Be stirred at room temperature in amine 6 it is small when；Or acyl chlorides and n,N-diisopropylethylamine are added into compound L, then the room in tetrahydrofuran Temperature is stirred overnight；
Step d2)：Oxidized compound P obtains compound Q, and usable dichloromethane makees solvent, and Dai Si-Martin's oxidant is made Oxidant, is stirred at room temperature reaction overnight；
Step e2)：Compound Q is carried out reduction amination with compound VI and obtain compound R, such as first to compound VI With adding sodium triacetoxy borohydride in Q, and it is stirred overnight at room temperature in 1,2- dichloroethanes.
Reaction equation 3：
Wherein, R2And R3Definition with the definition in general formula I, X is halogen, and G is any group,
And this method comprises the following steps：
Step a3)：With the step a1 in reaction equation 1)；
Step b3)：With the step b1 in reaction equation 1)；
Step c3)：Compound L is reacted from different sulfonic acid chlorides, obtain compound S, sulphur is first such as added into compound L Acyl chlorides and pyridine, and be stirred overnight at room temperature in methylene chloride；
Step d3)：Oxidized compound S obtains compound T, and usable dichloromethane makees solvent, and Dai Si-Martin's oxidant is made Oxidant, is stirred at room temperature reaction overnight；
Step e3)：Compound T and compound VI is carried out reduction amination and obtain compound U, such as first to compound VI With adding sodium triacetoxy borohydride in T, and it is stirred overnight at room temperature in 1,2- dichloroethanes.
An additional aspect of the present invention provides the preparation method of the polysubstituted aminated compounds shown in another general formula I, This method can be realized by formulas below：
Wherein, R1、R2、R3And R4Definition with the definition in general formula I,
And this method comprises the following steps：
Step a)：Make R3- CHO and R2-CH2-NH2Carry out reduction amination and obtain compound VI, such as first room in methyl alcohol Temperature stirring 0.5 it is small when after add sodium borohydride be stirred for 2 it is small when；
Step b)：Compound VI and compound II is carried out reduction amination and obtain compound I, such as use triacetyl oxygen Base sodium borohydride makees reduction amination reagent, and 1,2- methylene chloride as solvent, is stirred overnight at room temperature.
Specifically, above-mentioned preparation method can be realized by the method shown in formulas below：
Wherein, R1And R4Definition with the definition in general formula I,
And this method comprises the following steps：
Step 1)：2- amino -4- chloropyridines is carried out nitration reaction and obtain compound I, the concentrated sulfuric acid-concentrated nitric acid can be used to make Nitrating agent；
Step 2)：Compound I is carried out nucleophilic substitution with N methyl piperazine and obtain compound J, isopropanol can be used Make 90 DEG C of reactions of solvent；
Step 3)：Nitro in reducing compound J obtains compound K, and usable palladium carbon makees catalyst, methanol as solvent；
Step 4)：The glycine reactant that compound K is protected with benzyloxycarbonyl group (Cbz) is obtained compound L, benzo can be used Triazole-N, N, N', N'- tetramethylurea hexafluorophosphoric acid ester makees condensing agent, and n,N-diisopropylethylamine makees alkali, N, N- dimethyl methyls Acid amides makees solvent, and mixture stirs 24h at 50 DEG C；
Step 5)：Cbz protection groups in removing compound L obtain compound M, and usable palladium carbon makees catalyst, methanol-vinegar Acid makees solvent, is stirred overnight at room temperature under nitrogen atmosphere；
Step 6)：Nucleophilic substitution is carried out to compound M and obtains compound N, usable 2- (4- brombutyls) iso-indoles- 1,3- diketone makees electrophilic reagent, and sodium acid carbonate makees alkali, and n,N-Dimethylformamide is stirred overnight at room temperature as solvent；
Step 7)：Compound N is carried out reduction amination with compound II and obtain compound O, triacetyl oxygen can be used Base sodium borohydride makees reduction amination reagent, and 1,2- methylene chloride as solvent is stirred overnight at room temperature；
Step 8)：Compound O is deprotected to obtain compound P, usable hydrazine hydrate makees deprotecting regent, and ethanol is made Solvent, when reflux 2 is small.
An additional aspect of the present invention provides the preparation method of the polysubstituted aminated compounds shown in another general formula I, This method can be realized by formulas below：
Wherein, R1、R2、R3And R4Definition with the definition in general formula I,
And this method comprises the following steps：
Step a)：Make R2-CH2-NH2Reduction amination is carried out with compound II and obtains compound VII, such as first in methanol In be stirred at room temperature 0.5 it is small when after add sodium borohydride be stirred for 2 it is small when；
Step b)：Make compound VII and R3- CHO carries out reduction amination and obtains compound I, such as uses triacetyl oxygen Base sodium borohydride makees reduction amination reagent, and 1,2- methylene chloride as solvent is stirred overnight at room temperature.
Specifically, the preparation method of the polysubstituted aminated compounds shown in general formula I can pass through the side shown in formulas below Method is realized：
Wherein, R1、R3And R4Definition with the definition in general formula I,
And this method comprises the following steps：
Step 1)：2- amino -4- chloropyridines is carried out nitration reaction and obtain compound I, the concentrated sulfuric acid-concentrated nitric acid can be used to make Nitrating agent；
Step 2)：Compound I is carried out nucleophilic substitution with N methyl piperazine and obtain compound J, isopropanol can be used Make 90 DEG C of reactions of solvent；
Step 3)：Nitro in reducing compound J obtains compound K, and usable palladium carbon makees catalyst, methanol as solvent；
Step 4)：The glycine reactant that compound K is protected with Cbz is obtained compound L, benzotriazole-N can be used, N, N', N'- tetramethylurea hexafluorophosphoric acid ester make condensing agent, and n,N-diisopropylethylamine makees alkali, and n,N-Dimethylformamide is made molten Agent, mixture stir 24h at 50 DEG C；
Step 5)：Cbz protection groups in removing compound L obtain compound M, and palladium carbon can be made to make catalyst, methanol-acetic acid Make solvent, be stirred overnight at room temperature under nitrogen atmosphere；
Step 6)：Compound M and compound II is carried out reduction amination and obtain compound Q, triacetyl oxygen can be used Base sodium borohydride makees reduction amination reagent, 1,2- methylene chloride as solvent be stirred at room temperature 1 it is small when；
Step 7)：Make compound Q and R3- CHO carries out reduction amination and obtains compound R, and triacetoxyl group can be used Sodium borohydride makees reduction amination reagent, 1,2- methylene chloride as solvent be stirred at room temperature 2 it is small when.
Another aspect of the invention provides a kind of polysubstituted aminated compounds shown in general formula I or its and can pharmaceutically connect The purposes of salt, ester, prodrug and/or its hydrate received, it is mutual as the protein-protein between hiv integrase and LEDGF/p75 Effect and the inhibitor of hiv integrase dimerization, are preparing the purposes in being used to treat the medicine of AIDS.
It is used to treat AIDS-treating medicine composition it is still another aspect of the present invention to provide a kind of, it includes treatment to have Polysubstituted aminated compounds or its pharmaceutically acceptable salt, ester, prodrug shown in one or more general formula I of effect amount and/or its Hydrate, and can optionally further include pharmaceutically acceptable carrier or excipient.
It is still another aspect of the present invention to provide the protein-protein between a kind of hiv integrase and LEDGF/p75 is mutual Effect and the inhibitor of hiv integrase dimerization, it includes the polysubstituted amine shown in one or more general formula I of therapeutically effective amount Class compound or its pharmaceutically acceptable salt, ester, prodrug and/or its hydrate, and can optionally further include and can pharmaceutically connect The carrier or excipient received.
The method that an additional aspect of the present invention provides treatment AIDS, the described method includes apply therapeutically effective amount Polysubstituted aminated compounds or its pharmaceutically acceptable salt, ester, prodrug and/or its hydrate shown in general formula I or the present invention's Aforementioned pharmaceutical compositions are to patient.
Beneficial effect
Polysubstituted aminated compounds or its pharmaceutically acceptable salt, ester, prodrug shown in general formula I provided by the invention and Or its hydrate can effectively suppress the protein-protein interaction and hiv integrase two between hiv integrase and LEDGF/p75 Dimerization acts on, and has Anti-HIV-1 Active in cellular level, its mechanism of action is different from the anti-Chinese mugwort medicine of existing any type, It can be used for the treatment of AIDS.
Embodiment
With reference to specific embodiment, the invention will be further described.It is to be understood that these embodiments are merely to illustrate this Invent and do not limit the scope of the invention.
Compound1H-NMR and13The measurement of C-NMR spectroscopic datas uses Varian Mercury-300MHz or Varian Mercury-400MHz nmr determinations, CDCl3Or CD3OD is solvent, and TMS is internal standard.Mass spectrum EI-MS is used Finnigan MAT95 types mass spectrograph measure, ESI-MS using Finnigan LCQ Deca mass spectrographs measure, high resolution mass spectrum by Finnigan MAT Instrument measurings.The TLC tlc silica gels plate used is given birth to by Shandong Yantai fellow member of an association or organization's silica gel development corporation, Ltd. Production, model HSGF254；The normal phase column chromatography silica gel used produces for Qingdao marine chemical industry factory, model zcx-11,200- 300 mesh.
Agents useful for same is analytical reagents.Agents useful for same is purchased from：Sinopharm Chemical Reagent Co., Ltd., Tianjin Alfa Aesar chemical reagent Co., Ltd, splendid remote chemical Science and Technology Ltd., uncommon love (Shanghai) the chemical conversion industry Development Co., Ltd of ladder, Lark waffle Technology Co., Ltd..
Prepare embodiment
Embodiment 1
Compound 1：2- ((((3- (2- cyano ethyls) pyridine -2- bases) methyl) (methyl) amino) methyl) -1H- benzo miaows Azoles -1- carboxylic acid tert-butyl esters
Step a：3- (2- picoline -3- bases) acrylonitrile
By 3- bromine-2-methylpyridines (1.72g, 10mmol), acrylonitrile (3.29mL, 50mmol), palladium (244mg, 1mmol), tetrabutylammonium chloride (2.78g, 10mmol) and sodium acid carbonate (4.2g, 50mmol) are dissolved in 15mL N, N- dimethyl Formamide (DMF).Mixture is in N2It is placed under protection under the conditions of 110 DEG C of microwave and reacts 5h.After cooling, be spin-dried for DMF, residue with Water and dichloromethane (DCM) liquid separation, the drying of organic phase anhydrous sodium sulfate, filtering and concentrating, residue column chromatography obtain title compound Thing is white gum thing (1.33g, yield 93%).
1H NMR(300MHz,CDCl3,ppm):δ8.52-8.50(m,1.5H),8.18(d,0.5H,J=7.8Hz),7.72 (d,1H,J=7.8Hz),7.63(d,1H,J=16.5Hz),7.37(d,0.5H,J=11.7Hz),7.26-7.24(m,0.5H), 7.21-7.18(m,1H),5.83(d,1H,J=16.5Hz),5.64(d,0.5H,J=11.7Hz),2.62(s,3H),2.58(s, 1.5H).
Step b：3- (2- picoline -3- bases) propionitrile
3- (2- picoline -3- bases) acrylonitrile (1.278g, 8.88mmol) is dissolved in 10mL methanol, adds 511mgPd- C (palladium carbon), mixture vacuumizes change hydrogen three times after be stirred at room temperature 24h in a hydrogen atmosphere, cross and filter out Pd-C, filtrate concentration It is pale yellow oil (816mg, yield 63%) that column chromatography, which obtains title compound,.
1H NMR(300MHz,CDCl3,ppm):δ8.24(dd,1H,J1=5.1Hz,J2=1.5Hz),7.35(d,1H,J= 7.8Hz),7.00-6.95(m,1H),2.80(t,2H,J=7.2Hz),2.47(t,2H,J=7.2Hz),2.40(s.3H).
Step c：3- (2- cyano ethyls) -2- picoline 1- oxides
3- (2- picoline -3- bases) propionitrile (191mg, 1.30mmol) is dissolved in 4mL acetic acid, stirs lower addition 30% H2O2(0.68mL) (hydrogen peroxide), mixture stir reaction 5.5h at 80 DEG C, are spin-dried for after letting cool, and it is molten to add saturated sodium carbonate Liquid adjusts pH to neutrality, is extracted four times with DCM, merges organic phase, anhydrous sodium sulfate drying, filtering and concentrating obtains title compound and is Pale red solid (183mg, yield 87%), is directly used in next step.
Step d：Acetic acid (3- (2- cyano ethyls) pyridine -2- bases) methyl esters
3- (2- cyano ethyls) -2- picoline 1- oxides (961mg, 5.93mmol) are dissolved in 10mL aceticanhydrides, are mixed Thing stirs reaction 4h at 115 DEG C, is spin-dried for the direct column chromatography of solvent and obtains title compound as pale yellow oil (900mg, receipts Rate 74%).
1H NMR(300MHz,CDCl3,ppm):δ 8.56 (d, 1H, J=4.5Hz), 7.65 (d, 1H, J=7.5Hz), 7.33- 7.29(m,1H),5.27(s,2H),3.07(t,2H,J=7.2Hz),2.70(t,2H,J=7.2Hz),2.13(s,3H).
Step e：3- (2- (methylol) pyridin-3-yl) propionitrile
Acetic acid (3- (2- cyano ethyls) pyridine -2- bases) methyl esters (167mg, 0.82mmol) is dissolved in 4mL methanol, under stirring Sodium methoxide (44mg, 0.82mmol) is added, 2h is stirred at room temperature in mixture, is spin-dried for direct column chromatography and obtains title compound, is White gummy solid (93mg, yield 70%).
1H NMR(300MHz,CDCl3,ppm):δ8.47(d,1H,J=5.4Hz),7.62(d,1H,J=7.5Hz),7.29- 7.25(m,1H),4.76(s,2H),4.54(brs,1H),2.95(t,2H,J=7.2Hz),2.69(t,2H,J=7.2Hz).
Step f：3- (2- formylpyridine -3- bases) propionitrile
3- (2- (methylol) pyridin-3-yl) propionitrile (93mg, 0.57mmol) is dissolved in 5mLDCM, stirs lower addition DMP (Dai Si-Martin's oxidant) (266mg, 0.63mmol), mixture is in room temperature N2The lower stirring 2h of protection, is diluted with DCM, uses saturation Sodium acid carbonate is washed, and organic phase anhydrous sodium sulfate drying, filtering and concentrating residue column chromatography obtains title compound, is light green oil Shape thing (90mg, yield 98%).
1H NMR(300MHz,CDCl3,ppm):δ10.03(s,1H),8.67(d,1H,J=4.5Hz),7.68(d,1H,J= 7.8Hz),7.44-7.40(m,1H),3.25(t,2H,J=7.2Hz),2.65(t,2H,J=7.2Hz).
Step g：3- (2- ((methylamino) methyl) pyridin-3-yl) propionitrile
Under stirring, to 1, the 2- dichloroethanes (3mL) of 3- (2- formylpyridine -3- bases) propionitrile (86mg, 0.537mmol) Sequentially added in solution methylethylolamine solution (154 μ L, 1.07mmol) and sodium triacetoxy borohydride (171mg, 0.805mmol), 24h is stirred at room temperature in mixture.Solvent evaporated, gained residue column chromatography obtain title compound (63mg, yield 67%) is faint yellow jelly.
1H NMR(300MHz,CDCl3)δ8.40(s,1H),7.54-7.51(m,1H),7.20-7.15(m,1H),3.82 (s,2H),2.96-2.93(m,2H),2.70-2.64(m,2H),2.44(s,3H).
Step h：2- (chloromethyl) -1H- benzimidazole -1- carboxylic acid tert-butyl esters
In 0 DEG C, to 2- (chloromethyl)-benzimidazole (224mg, 1.34mmol, 1eq), di-tert-butyl dicarbonate (587mg, 2.68mmol, 2eq) and dichloromethane (6mL) solution of triethylamine (372 μ L, 2.68mmol) in add catalytic amount 4- diformazans Reaction 2h is stirred at room temperature in aminopyridine, mixture.Ethyl acetate dilution is added, successively with saturated sodium bicarbonate solution and saturation Salt is washed, anhydrous sodium sulfate drying, filtering and concentrating, and gained crude product (yellow oil, yield 67%) is directly used in next step Reaction.
Step i：2- ((((3- (2- cyano ethyls) pyridine -2- bases) methyl) (methyl) amino) methyl) -1H- benzo miaows Azoles -1- carboxylic acid tert-butyl esters
Under stirring, to 2- (chloromethyl) -1H- benzimidazole -1- carboxylic acid tert-butyl esters (40mg, 0.228mmol) and 3- (2- ((methylamino) methyl) pyridin-3-yl) propionitrile (91mg, 0.342mmol) acetonitrile (8mL) solution in sequentially add N, N- is different Propylethylamine (75 μ L, 0.456mmol) and potassium iodide (4mg, 0.0228mmol).Mixture stirs reaction 12h at 60 DEG C, steams Dry solvent, it is faint yellow jelly (58mg, yield 63%) that residue column chromatography, which obtains title compound,.
1H NMR(300MHz,CDCl3)δ8.46(d,1H,J=4.5Hz),7.90-7.87(m,1H),7.75-7.72(m, 1H),7.60(d,1H,J=7.8Hz),7.36-7.33(m,2H),7.26-7.21(m,1H),4.38(s,2H),4.18(s,2H), 3.10(t,2H,J=6.9Hz),2.73(t,2H,J=6.9Hz),2.53(s,3H),1.72(s,9H).
Embodiment 2
Compound 2：3- (2- ((((1H- benzimidazolyl-2 radicals-yl) methyl) (methyl) amino) methyl) pyridin-3-yl) propionitrile
Under 0 DEG C of stirring, to 3- (2- cyano ethyls) pyridine -2- bases) methyl) (methyl) amino) methyl) -1H- benzo miaows In the 5mL dichloromethane solutions of azoles -1- carboxylic acid tert-butyl esters (42mg, 0.104mmol) add trifluoroacetic acid (119 μ L, 1.55mmol), 2h is stirred at room temperature in mixture.Solvent and remaining trifluoroacetic acid are spin-dried for, residue saturated sodium carbonate is molten Liquid neutralizes, and after water is mutually extracted three times with dichloromethane, merges organic phase, anhydrous sodium sulfate drying, filtering and concentrating, residue column layer It is faint yellow jelly (28mg, yield 90%) that analysis, which obtains title compound,.
1H NMR(300MHz,CDCl3)δ10.15(brs,1H),8.57(d,1H,J=4.5Hz),7.65-7.62(m,3H), 7.32-7.23(m,3H),3.88(s,2H),3.80(s,2H),3.06(t,2H,J=6.9Hz),2.77(t,2H,J=6.9Hz), 2.42(s,3H);13C NMR(100MHz,CDCl3,ppm):δ155.3,149.9,147.3,138.5,136.9,133.9, 123.5,122.9,118.8,115.0,58.4,52.1,43.0,27.5,18.4;EI-MS:305(M+);HRMS(EI):Calculate Value：C18H19N5(M)+:305.1640;Measured value：305.1646.
Embodiment 3
Compound 3：3- (2- (((isoquinolyl-1 methyl) (methyl) amino) methyl) pyridin-3-yl) propionitrile
Under stirring, to isoquinolin -1- formaldehyde (32mg, 0.183mmol) and 3- (2- ((methylamino) methyl) pyridine -3- Base) propionitrile (57mg, 0.365mmol) 1,2- dichloroethanes 2mL solution in sequentially add acetic acid (10.6 μ L, 0.183mmol) With sodium triacetoxy borohydride (116mg, 0.549mmol), 24h is stirred at room temperature in mixture.Solvent evaporated, residue column It is yellow oil (36mg, yield 63%) that chromatography, which obtains title compound,.
1H NMR(300MHz,CDCl3)δ8.94-8.91(m,2H),8.52(d,1H,J=8.1Hz),8.28(d,1H,J= 7.8Hz),8.15-7.95(m,4H),7.67-7.63(m,1H),4.72(s,2H),4.36(s,2H),3.19-3.17(m,2H), 2.82-2.80(m,5H);13C NMR(100MHz,CDCl3,ppm):δ157.2,156.0,147.4,141.4,137.5, 136.2,133.4,130.1,127.2,125.4,122.9,120.7,118.9,62.1,61.8,43.1,27.2,18.0;EI- MS:316(M+);HRMS(EI):Calculated value：C20H20N4(M)+:316.1688;Measured value：316.1685.
The preparation flow of wherein isoquinolin -1- formaldehyde is as follows：
By SeO2(757mg, 6.82mmol) and 1- methylisoquinoliniums (698mg, 4.87mmol) are dissolved in dioxane (10mL), mixture are refluxed 16h, and cold filtration, filtrate concentration, it is solid for white that residue column chromatography obtains title compound Body (485mg, yield 63%).
1H NMR(300MHz,CDCl3,ppm):δ10.29(s,1H),9.18(d,1H,J=8.7Hz),8.63(d,1H,J= 5.1Hz),7.78-7.74(m,2H),7.66-7.59(m,2H).
Embodiment 4
Compound 4：3- (2- (((benzothiazole -2- ylmethyls) (methyl) amino) methyl) pyridin-3-yl) propionitrile
Reaction process is same as Example 1, only in step i with 2- (bromomethyl) benzothiazole replace 2- (chloromethyl)- 1H- benzimidazole -1- carboxylic acid tert-butyl esters, it is pale yellow oil (72mg, yield 97%) to obtain title compound.
1H NMR(300MHz,CDCl3,ppm):δ 8.47 (d, 1H, J=4.8Hz), 7.97 (d, 1H, J=8.1Hz), 7.86 (d, 1H, J=7.8Hz), 7.62 (d, 1H, J=7.8Hz), 7.45 (t, 1H, J=7.8Hz), 7.36 (t, 1H, J=7.2Hz), 7.26-7.22 (m, 1H), 4.07 (s, 2H), 3.95 (s, 2H), 3.19 (t, 2H, J=7.2Hz), 2.84 (t, 2H, J= 7.2Hz),2.36(s,3H);EI-MS:322(M)+;HRMS(EI):Calculated value：C18H18N4S(M)+:322.1252;Measured value： 322.1259.
Embodiment 5
Compound 5：3- (2- ((methyl (quinoline -2- ylmethyls) amino) methyl) pyridin-3-yl) propionitrile
Reaction process is same as Example 3, only replaces isoquinolin -1- formaldehyde with 2- quinoline aldehydes, obtains title compound For yellow oil (64mg, yield 80%).
1H NMR(300MHz,CDCl3,ppm):δ 8.44 (s, 1H), 8.13 (d, 1H, J=8.7Hz), 8.05 (d, 1H, J= 8.1Hz), 7.78 (d, 1H, J=7.8Hz), 7.68-7.66 (m, 1H), 7.52-7.45 (m, 3H), 7.19-7.15 (m, 1H), 3.90(s,2H),3.83(s,2H),3.02-2.97(m,2H),2.76-2.71(m,2H),2.25(s,3H);EI-MS:316(M )+;HRMS(EI):Calculated value：C20H20N4(M)+:316.1688;Measured value：316.1685.
Embodiment 6
Compound 6：3- (2- ((methyl (pyridine -2- ylmethyls) amino) methyl) pyridin-3-yl) propionitrile
Reaction process is same as Example 3, only replaces isoquinolin -1- formaldehyde with 2- pyridine carboxaldehydes, obtains title compound For faint yellow jelly (28mg, yield 74%).
1H NMR(300MHz,CDCl3,ppm):δ 8.61 (d, 1H, J=4.8Hz), 8.48 (d, 1H, J=4.5Hz), 7.71 (t, 1H, J=7.5Hz), 7.58 (d, 1H, J=7.8Hz), 7.41 (d, 1H, J=7.8Hz), 7.27-7.22 (m, 2H), 3.94 (s, 2H), 3.89 (s, 2H), 3.02 (t, 2H, J=7.2Hz), 2.77 (t, 2H, J=7.2Hz), 2.36 (s, 3H);EI-MS: 266(M)+;HRMS(EI):Calculated value：C16H18N4(M)+:266.1531;Measured value：266.1524.
Embodiment 7
Compound 7：3- (2- ((((1H- indol-3-yls) methyl) (methyl) amino) methyl) pyridin-3-yl) propionitrile
Reaction process is same as Example 3, only replaces isoquinolin -1- formaldehyde with 3- indolecarboxaldehydes, obtains title compound For colorless gum (30mg, yield 48%).
1H NMR(300MHz,CDCl3,ppm):δ 8.52 (brs, 1H), 8.46 (d, 1H, J=4.5Hz), 7.56 (d, 1H, J =7.2Hz), 7.50 (d, 1H, J=7.5Hz), 7.40 (d, 1H, J=8.1Hz), 7.31 (s, 1H), 7.22-7.10 (m, 3H), 3.87 (s, 2H), 3.78 (s, 2H), 2.78 (t, 2H, J=7.2Hz), 2.37 (t, 2H, J=7.2Hz), 2.28 (s, 3H);EI- MS:304(M)+;HRMS(EI):Calculated value：C19H20N4(M)+:304.1685;Measured value：304.1688.
Embodiment 8
Compound 8：3- (2- ((((1H- imidazoles -2- bases) methyl) (methyl) amino) methyl) pyridin-3-yl) propionitrile
Reaction process is same as Example 3, only replaces isoquinolin -1- formaldehyde with 2- imidazole formaldehydes, obtains title compound For colorless gum (30mg, yield 55%).
1H NMR(300MHz,CDCl3,ppm):δ 11.00 (brs, 1H), 8.52 (d, 1H, J=4.2Hz), 7.65 (d, 1H, ), J=7.8Hz 7.31-7.26 (m, 1H), 7.07 (s, 2H), 3.68 (s, 2H), 3.60 (s, 2H), 3.05 (t, 2H, J= 7.2Hz), 2.82 (t, 2H, J=7.2Hz), 2.35 (s, 3H);EI-MS:255(M)+;HRMS(EI):Calculated value：C14H17N5(M )+:255.1484;Measured value：255.1479.
Embodiment 9
Compound 9：3- (2- (((benzoxazole -2- ylmethyls) (methyl) amino) methyl) pyridin-3-yl) propionitrile
Reaction process is same as Example 1, and only with 2-, (bromomethyl) benzoxazoles replace 2- (chloromethyl) -1H- benzo miaows Azoles -1- carboxylic acid tert-butyl esters, it is yellow jelly (28mg, yield 46%) to obtain title compound.
1H NMR(300MHz,CDCl3,ppm):δ 8.44 (d, 1H, J=3.9Hz), 7.71-7.69 (m, 1H), 7.60- 7.53(m,2H),7.33-7.31(m,2H),7.23-7.19(m,1H),3.92(s,2H),3.90(s,2H),3.05(t,2H,J =7.2Hz), 2.86 (t, 2H, J=7.2Hz), 2.33 (s, 3H);EI-MS:306(M)+;HRMS(EI):Calculated value：C18H18N4O (M)+:306.1481;Measured value：306.1473.
(preparation flow of bromomethyl) benzoxazoles is as follows by wherein 2-：
Under stirring, into carbon tetrachloride (16mL) solution of 2- Jia bases benzoxazoles (665mg, 5mmol), N- bromos are added Succimide (890mg, 5mmol) and azo isobutyl dintrile (188mg, 1.15mmol), mixture are refluxed reaction 12h. Let cool, filter, filtrate concentration, it is pale yellow oil (471mg, yield 45%) that residue column chromatography, which obtains title compound,.
1H NMR(300MHz,CDCl3,ppm):δ7.74-7.71(m,1H),7.54-7.50(m,1H),7.37-7.36(m, 2H),4.58(s,2H).
Embodiment 10
Compound 10：3- (2- ((((1H- imidazoles [4,5-b] pyridine -2- bases) methyl) (methyl) amino) methyl) pyridine - 3- yls) propionitrile
Step a：2- (2-aminopyridine -3- bases amino) -2- oxoethylamino benzyl formates
Under stirring, to benzyloxycarbonyl group protect glycine (1.80g, 8.6mmol) and 2,3- diamino-pyridine (894mg, In n,N-Dimethylformamide (20mL) solution 8.19mmol), benzotriazole-N, N, N', N'- tetramethylurea hexafluoro is added Phosphate (3.728g, 9.83mmol) and n,N-diisopropylethylamine DIPEA (2.707mL, 16.38mmol), mixture is 40 Stirring reaction 2 days under the conditions of DEG C.Solvent evaporated, is diluted with dichloromethane, successively with saturated sodium bicarbonate solution and saturated common salt Washing, the drying of organic phase anhydrous sodium sulfate, filtering and concentrating, residue column chromatography obtain title compound and (are received for faint yellow solid Rate 75%).
1H NMR(300MHz,CD3OD,ppm):δ8.46(s,1H),7.78(d,1H,J=5.1Hz),7.44(d,1H,J= 6.3Hz),7.28(s,4H),6.56-6.51(m,1H),6.22(s,1H),5.06(s,2H),3.92(d,2H,J=5.1Hz), 3.70(brs,2H).
Step b：(3H- imidazos [4,5-b] pyridine -2- bases) methyl carbamic acid benzyl ester
2- (2-aminopyridine -3- bases amino) -2- oxoethylaminos benzyl formate (1.138g) is dissolved in 32mL acetic acid, Mixture is refluxed reaction 8h, and solvent evaporated, it is white solid (525mg, yield that residue column chromatography, which obtains title compound, 50%)。
Step c：(3H- imidazos [4,5-b] pyridine -2- bases) methylamine
(3H- imidazos [4,5-b] pyridine -2- bases) methyl carbamic acid benzyl ester (318mg, 1.12mmol) is dissolved in In 4NHBr/AcOH (12.5mL) solution, 1.5h is stirred at room temperature in mixture.Solvent is evaporated off, residue column chromatography obtains title Compound is white powdery solids (yield 75%).
1H NMR(300MHz,CD3OD,ppm):δ8.31-8.29(m,1H),7.95-7.92(m,1H),7.27-7.22(m, 1H),4.16(s,2H).
Step d：3- (2- (((3H- imidazoles [4,5-b] pyridine -2- bases) methylamino) methyl) pyridin-3-yl) propionitrile
Under stirring, to (3H- imidazos [4,5-b] pyridine -2- bases) methylamine (66mg, 0.44mmol) and 3- (2- formoxyls Pyridin-3-yl) propionitrile (47mg, 0.29mmol, building-up process is with embodiment 1) 1,2- dichloroethanes (5mL) solution in add Sodium triacetoxy borohydride (95mg, 0.45mmol), 24h is stirred at room temperature in mixture.Solvent evaporated, residue column chromatography It is faint yellow jelly (25mg, yield 30%) to obtain title compound.
1H NMR(300MHz,CDCl3,ppm):δ8.50(dd,1H,J1=4.8Hz,J2=1.8Hz),8.30(dd,1H,J1= 4.8Hz,J2=1.8Hz),7.95(dd,1H,J1=7.8Hz,J2=1.5Hz),7.52(dd,1H,J1=7.8Hz,J2=1.5Hz), 7.22-7.11 (m, 2H), 4.23 (s, 2H), 4.02 (s, 2H), 2.91 (t, 2H, J=7.2Hz), 2.59 (t, 2H, J= 7.2Hz).
Step e：3- (2- ((((3H- imidazoles [4,5-b] pyridine -2- bases) methyl) (methyl) amino) methyl) pyridine -3- Base) propionitrile
Under stirring, to 3- (2- (((3H- imidazoles [4,5-b] pyridine -2- bases) methylamino) methyl) pyridin-3-yl) propionitrile Triacetoxy borohydride is added in 1,2- dichloroethanes (5mL) solution of (25mg, 0.089mmol) and formaldehyde (8 μ L, 0.11mmol) Sodium hydride (29mg, 0.134mmol), 24h is stirred at room temperature in mixture.Solvent evaporated, residue column chromatography obtain titled Compound is faint yellow jelly (22mg, yield 85%).
1H NMR(300MHz,CDCl3,ppm):δ8.60-8.58(m,1H),8.36-8.34(m,1H),7.97(d,1H,J =8.1Hz), 7.65 (dd, 1H, J1=7.8Hz,J2=1.5Hz),7.32-7.28(m,1H),7.21-7.16(m,1H),3.83(s, 2H), 3.80 (s, 2H), 3.70 (s, 3H), 3.08 (t, 2H, J=7.2Hz), 2.79 (t, 2H, J=7.2Hz), 2.43 (s, 3H); ESI-MS:307.2(M+H)+;HRMS(ESI):Calculated value：C17H18N6Na(M+Na)+:329.1491;Measured value：329.1504.
Embodiment 11
Compound 11：2- ((methyl ((3- picoline -2- bases) methyl) amino) methyl) -1H- benzimidazole -1- carboxylic acids The tert-butyl ester
Step a：N- methyl isophthalic acids-(3- picoline -2- bases) methylamine
Methylethylolamine solution is added into methanol (2mL) solution of 3- methyl -2- pyridine carboxaldehydes (1mmol, 121mg, 1eq) (300 μ L, 2mmol, 2eq), mixture add sodium borohydride (38mg, 1mmol, 1eq) after 2h is stirred at room temperature, and mixture stirs again Mix 1h.After completion of the reaction, adding water quenching and go out and be evaporated off methanol after reaction, water mutually with after dichloromethane extraction three times, merges organic phase, Anhydrous sodium sulfate is dried, and filtering and concentrating, it is yellow oil (yield 58%) that residue column chromatography, which obtains title compound,.
1H NMR(300MHz,CDCl3)δ8.34(d,1H,J=4.5Hz),7.38(d,1H,J=6.6Hz),7.05-7.01 (m,1H),3.80(s,2H),2.88(s,1H),2.48(s,3H),2.26(s,3H).
Step b：2- ((methyl ((3- picoline -2- bases) methyl) amino) methyl) -1H- benzimidazole -1- carboxylic acid uncles Butyl ester
Reaction process is identical with step i in embodiment 1, only replaces 3- with N- methyl isophthalic acids-(3- picoline -2- bases) methylamine It is colorless gum (yield 60%) that (2- ((methylamino) methyl) pyridin-3-yl) propionitrile, which obtains title compound,.
1H NMR(300MHz,CDCl3,ppm):δ8.34(dd,1H,J1=4.8Hz,J2=1.2Hz),7.88-7.84(m, 1H), 7.74-7.71 (m, 1H), 7.37 (d, 1H, J=7.8Hz), 7.32-7.29 (m, 2H), 7.08-7.04 (m, 1H), 4.22 (s,2H),3.87(s,2H),2.35(s,3H),2.27(s,3H),1.69(s,9H).
Embodiment 12
Compound 12：N- ((1H- benzimidazolyl-2 radicals-yl) methyl)-N- methyl isophthalic acids-(3- picoline -2- bases) methylamine
Reaction process is same as Example 2, only with 2- ((methyl ((3- picoline -2- bases) methyl) amino) methyl) - 1H- benzimidazole -1- carboxylic acid tert-butyl esters replace 3- (2- cyano ethyls) pyridine -2- bases) methyl) (methyl) amino) methyl) -1H- It is faint yellow jelly (yield 57%) that benzimidazole -1- carboxylic acid tert-butyl esters, which obtain title compound,.
1H NMR(300MHz,CDCl3,ppm):δ 8.52 (d, 1H, J=4.5Hz), 7.62 (brs, 2H), 7.53 (d, 1H, J =7.2Hz), 7.26-7.18 (m, 3H), 3.87 (s, 2H), 3.76 (s, 2H), 2.46 (s, 3H), 2.42 (s, 3H);EI-MS: 266(M)+;HRMS(EI):Calculated value：C16H18N4(M)+:266.1531;Measured value：266.1527.
Embodiment 13
Compound 13：2- ((methyl (pyridine -2- ylmethyls) amino) methyl) -1H- benzimidazole -1- carboxylic acid tert-butyl esters
2- pyridine carboxaldehydes are only replaced 3- methyl -2- pyridine carboxaldehydes, obtain title compound by reaction process with embodiment 11 For faint yellow jelly (yield 64%).
1H NMR(300MHz,CDCl3,ppm):δ 8.51 (d, 1H, J=4.8Hz), 7.89-7.86 (m, 1H), 7.76- 7.73(m,1H),7.60(td,1H,J1=7.8Hz,J2=2.1Hz), 7.51 (d, 1H, J=7.8Hz), 7.33-7.30 (m, 2H), 7.12 (t, 1H, J=6.0Hz), 4.22 (s, 2H), 3.91 (s, 2H), 2.42 (s, 3H), 1.70 (s, 9H)
Embodiment 14
Compound 14：N- ((1H- benzimidazolyl-2 radicals-yl) methyl)-N- methyl isophthalic acids-(pyridine -2- bases) methylamine
Reaction process is same as Example 2, only with 2- ((methyl (pyridine -2- ylmethyls) amino) methyl) -1H- benzo miaows Azoles -1- carboxylic acid tert-butyl esters replace 3- (2- cyano ethyls) pyridine -2- bases) methyl) (methyl) amino) methyl) -1H- benzimidazoles - 1- carboxylic acid tert-butyl esters, it is yellow jelly (yield 96%) to obtain title compound.
1H NMR(300MHz,CDCl3,ppm):δ 8.67 (d, 1H, J=4.5Hz), 7.69 (t, 2H, J=7.8Hz), 7.56 (brs, 1H), 7.33 (d, 1H, J=7.8Hz), 7.27-7.21 (m, 3H), 3.96 (s, 2H), 3.74 (s, 2H), 2.40 (s, 3H);ESI-MS:253.2(M+H)+;HRMS(ESI):Calculated value：C15H16N4Na(M+Na)+:275.1273;Measured value： 275.1277.
Embodiment 15
Compound 15：2- ((methyl (5,6,7,8- tetrahydroquinoline -8- bases) amino) methyl) -1H- benzimidazole -1- carboxylic acids The tert-butyl ester
Step a：N- methyl -5,6,7,8- tetrahydroquinoline -8- amine
6,7- dihydroquinoline -8 (5H) -one (735mg, 5mmol) is dissolved in 10mL1,2- dichloroethanes, sequentially adds methylamine Ethanol solution (1.45mL, 10mmol), acetic acid HOAc (290 μ L, 5mmol) and sodium triacetoxy borohydride (2.12g, 10mmol).Gained mixture is stirred at room temperature 24h, adds saturated sodium bicarbonate solution tune PH to 10, liquid separation, water mutually again with Dichloromethane extracts three times, merges organic phase, anhydrous sodium sulfate is dry and is concentrated under reduced pressure.Concentrate is through column chromatography chromatogram point From it is yellow oil to obtain title compound.(688mg, yield 85%).
1H-NMR(CDCl3):δ8.34(d,1H,J=3.6Hz),7.32(d,1H,J=7.8Hz),7.03-6.99(m,1H), 3.62(t,1H,J=6.3Hz),2.76-2.69(m,2H),2.64(s,1H),2.48(s,3H),2.12-1.91(m,2H), 1.79-1.65(m,2H).
Step b：2- ((methyl (5,6,7,8- tetrahydroquinoline -8- bases) amino) methyl) -1H- benzimidazole -1- carboxylic acid uncles Butyl ester
Reaction process is with step b in embodiment 11, only by N- methyl -5,6,7,8- tetrahydroquinoline -8- amine replace N- methyl - 1- (3- picoline -2- bases) methylamine, it is colorless gum (yield 84%) to obtain title compound.
1H NMR(300MHz,CDCl3,ppm):δ 8.42 (d, 1H, J=3.3Hz), 7.88-7.84 (m, 1H), 7.73- 7.70 (m, 1H), 7.32-7.26 (m, 3H), 7.03-6.99 (m, 1H), 4.58 (d, 1H, J=15.6Hz), 4.47 (d, 1H, J= 15.6Hz),4.22-4.17(m,1H),2.81-2.63(m,2H),2.38(s,3H),2.18-2.11(m,1H),2.05-1.88 (m,2H),1.74-1.70(m,1H),1.68(s,9H).
Embodiment 16
Compound 16：N- ((1H- benzimidazolyl-2 radicals-yl) methyl)-N- methyl -5,6,7,8- tetrahydroquinoline -8- amine
Reaction process is same as Example 2, only with 2- ((methyl (5,6,7,8- tetrahydroquinoline -8- bases) amino) methyl) - 1H- benzimidazole -1- carboxylic acid tert-butyl esters replace 3- (2- cyano ethyls) pyridine -2- bases) methyl) (methyl) amino) methyl) -1H- Benzimidazole -1- carboxylic acid tert-butyl esters, it is yellow oil (yield 89%) to obtain title compound.
1H NMR(300MHz,CDCl3,ppm):δ 9.21 (brs, 1H), 8.50 (d, 1H, J=4.8Hz), 7.57-7.54 (m, 2H), 7.39 (d, 1H, J=7.2Hz), 7.17-7.08 (m, 3H), 4.11-3.90 (m, 3H), 2.86-2.63 (m, 2H), 2.32(s,3H),2.10-1.85(m,3H),1.72-1.60(m,1H);EI-MS:292(M)+;HRMS(EI):Calculated value： C18H20N4(M)+:292.1688;Measured value：292.1695.
Embodiment 17
Compound 17：2- ((((3- bromopyridine -2- bases) methyl) (methyl) amino) methyl) -1H- benzimidazole -1- carboxylic acids The tert-butyl ester
3- bromo-2-pyridyls formaldehyde is only replaced 3- methyl -2- pyridine carboxaldehydes, obtains title by reaction process with embodiment 11 Compound is colorless gum (yield 69%).
1H NMR(300MHz,CDCl3,ppm):δ 8.47 (d, 1H, J=4.8Hz), 7.87-7.85 (m, 1H), 7.79- 7.72(m,2H),7.31-7.29(m,2H),7.04-7.00(m,1H),4.32(s,2H),4.04(s,2H),2.51(s,3H), 1.68(s,9H).
Embodiment 18
Compound 18：N- ((1H- benzimidazolyl-2 radicals-yl) methyl) -1- (3- bromopyridine -2- bases)-N- methyl methylamines
Reaction process is same as Example 2, only with 2- ((((3- bromopyridine -2- bases) methyl) (methyl) amino) methyl) - 1H- benzimidazole -1- carboxylic acid tert-butyl esters replace 3- (2- cyano ethyls) pyridine -2- bases) methyl) (methyl) amino) methyl) -1H- Benzimidazole -1- carboxylic acid tert-butyl esters, it is colorless gum (yield 83%) to obtain title compound.
1H NMR(300MHz,CDCl3,ppm):δ 8.62 (d, 1H, J=4.2Hz), 7.92 (d, 1H, J=7.8Hz), 7.59-7.58(m,2H),7.26-7.21(m,2H),7.18-7.14(m,1H),4.01(s,2H),3.96(s,2H),2.48(s, 3H);ESI-MS:331.1(M)+;HRMS(ESI):Calculated value：C15H16BrN4(M+H)+:331.0558;Measured value： 331.0568.
Embodiment 19
Compound 19：3- (2- ((((3- bromopyridine -2- bases) methyl) (methyl) amino) methyl) -1H- benzimidazoles -1- Base) propionitrile
By 2- ((((3- bromopyridine -2- bases) methyl) (methyl) amino) methyl) -1H- benzimidazole -1- carboxylic acid tert-butyl esters (66mg, 0.153mmol, preparation process are shown in embodiment 17), acrylonitrile (50 μ L, 0.766mmol), palladium (4mg, 0.0153mmol), tetrabutylammonium chloride (43mg, 0.153mmol) and sodium acid carbonate (64mg, 0.766mmol) are placed in 2mL In DMF solution, 2h is reacted in stirring to mixture under 110 DEG C of blanket of nitrogen under microwave condition.Solvent is evaporated off, residue is dilute with water Release, dichloromethane extracts three times, merges organic phase, anhydrous sodium sulfate drying, filtering and concentrating, residue column chromatography obtains titled Compound is faint yellow solid (45mg, yield 78%).
1H NMR(300MHz,CDCl3,ppm):δ 8.60 (d, 1H, J=4.2Hz), 7.92 (d, 1H, J=7.8Hz), 7.74 (d, 1H, J=7.8Hz), 7.35-7.26 (m, 3H), 7.17-7.13 (m, 1H), 4.58 (t, 2H, J=7.5Hz), 3.99 (s, 2H), 3.94 (s, 2H), 2.95 (t, 2H, J=7.5Hz), 2.32 (s, 3H);ESI-MS:384.1(M+1)+;HRMS(ESI):Meter Calculation value：C18H18N5BrNa(M+Na)+:406.0643;Measured value：406.0654.
Embodiment 20
Compound 20：3- (2- ((((1H- benzimidazolyl-2 radicals-yl) methyl) (methyl) amino) methyl) pyridin-3-yl) third Sour methyl esters
By 2- ((((3- (2- cyano ethyls) pyridine -2- bases) methyl) (methyl) amino) methyl) -1H- benzimidazoles -1- Carboxylic acid tert-butyl ester (85mg, 0.21mmol, preparation process are shown in embodiment 1) is dissolved in 5mL concentrated hydrochloric acids, and mixture is refluxed reaction 12h.Let cool, solvent evaporated, then add 20mL methanol, mixture is refluxed reaction 2h.Let cool, solvent is evaporated in vacuo, it is residual It is white gummy solid (26mg, yield 37%) that excess column chromatography, which obtains title compound,.
1H NMR(300MHz,CDCl3,ppm):δ 12.36 (brs, 1H), 9.23 (d, 1H, J=3.9Hz), 8.46 (brs, 1H), 7.70 (d, 1H, J=7.8Hz), 7.51-7.49 (m, 1H), 7.35 (t, 1H, J=6.3Hz), 7.12-7.09 (m, 2H), 4.30 (s, 2H), 3.92 (s, 2H), 3.60 (s, 3H), 2.94 (t, 2H, J=7.2Hz), 2.56 (t, 2H, J=7.2Hz), 2.43 (s,3H);ESI-MS:339.2(M+1)+;HRMS(ESI):Calculated value：C19H23N4O2(M+H)+:339.1821;Measured value： 339.1821.
Embodiment 21
Compound 21：3- (2- ((((1H- benzimidazolyl-2 radicals-yl) methyl) (methyl) amino) methyl) pyridin-3-yl) third Acid
By 2- ((((3- (2- cyano ethyls) pyridine -2- bases) methyl) (methyl) amino) methyl) -1H- benzimidazoles -1- Carboxylic acid tert-butyl ester (139mg, 0.34mmol, preparation process are shown in embodiment 1) is dissolved in 2N NaOH's (1.5mL) and EtOH (1.5mL) In the mixed solvent, mixture are refluxed reaction 10h.Let cool, ethanol is evaporated in vacuo, add 1N hydrochloric acid and adjust PH to 3.Mixture Concentration, residue are dissolved in methanol, filter out insoluble matter, it is pale yellow powder shape solid that filtrate concentration column chromatography, which obtains title compound, (yield 60%).
1H NMR(300MHz,CD3OD,ppm):δ 8.40 (d, 1H, J=4.2Hz), 7.78 (d, 1H, J=7.2Hz), 7.63-7.60 (m, 2H), 7.38-7.32 (m, 3H), 4.24 (s, 2H), 4.20 (s, 2H), 3.04 (t, 2H, J=7.2Hz), 2.57 (t, 2H, J=7.2Hz), 2.48 (s, 3H);ESI-MS:325.2(M+1)+
Embodiment 22
Compound 23：3- (2- ((((1H- benzimidazolyl-2 radicals-yl) methyl) (methyl) amino) methyl) pyridin-3-yl)-N- Cyclopropyl propionamide
Under stirring, to 3- (2- ((((1H- benzimidazolyl-2 radicals-yl) methyl) (methyl) amino) methyl) pyridin-3-yl) third In DMF (2mL) solution of sour (25mg, 0.077mmol), three (dimethylamino) phosphorus of benzotriazole -1- bases epoxide is added Hexafluorophosphate (40mg, 0.093mmol) and n,N-diisopropylethylamine (49mg, 0.385mmol), mixture stirs at room temperature Mix 20 minutes, then add cyclopropylamine (13mg, 0.231mmol), mixture is stirred for 12h.Be evaporated in vacuo solvent, residue with Dichloromethane and moisture liquid, water are mutually extracted twice with dichloromethane again, merge organic phase, anhydrous sodium sulfate drying, filtering and concentrating It is white gum thing (12mg, yield 43%) that column chromatography, which obtains title compound,.
1H NMR(300MHz,CDCl3,ppm):δ 8.41 (d, 1H, J=4.8Hz), 7.64-7.61 (m, 2H), 7.47 (d, 1H, J=7.5Hz), 7.23-7.14 (m, 3H), 6.81 (s, 1H), 3.90 (s, 2H), 3.81 (s, 2H), 3.12 (t, 2H, J= 7.8Hz), 2.83-2.76 (m, 1H), 2.56 (t, 2H, J=7.8Hz), 2.23 (s, 3H), 0.83-0.77 (m, 2H), 0.54- 0.49(m,2H);ESI-MS:364.2(M+H)+;HRMS(ESI):Calculated value：C21H26N5O(M+H)+:364.2137;Measured value： 364.2130.
Embodiment 23
Compound 22：3- (2- ((((1H- benzimidazolyl-2 radicals-yl) methyl) (methyl) amino) methyl) pyridin-3-yl) third Acid amides
Reaction process is identical with embodiment 22, only replaces cyclopropylamine with saturation ammonia methanol solution, obtains title compound For white gum thing (yield 30%).
1H NMR(300MHz,CD3OD,ppm):δ 8.40 (d, 1H, J=4.2Hz), 7.78 (d, 1H, J=7.2Hz), 7.63-7.60 (m, 2H), 7.38-7.32 (m, 3H), 4.20 (s, 2H), 4.13 (s, 2H), 3.08 (t, 2H, J=7.8Hz), 2.60 (t, 2H, J=7.8Hz), 2.45 (s, 3H);ESI-MS:324.2(M+1)+;HRMS(ESI):Calculated value：C18H22N5O(M+ H)+:324.1824;Measured value：324.1837.
Embodiment 24
Compound 24：3- (2- ((((1H- benzimidazolyl-2 radicals-yl) methyl) (methyl) amino) methyl) pyridin-3-yl)-N, N- dimethylpropionamides
Reaction process is identical with embodiment 23, only replaces cyclopropylamine with dimethylamine hydrochloride, it is white to obtain title compound Color jelly.
1H NMR(300MHz,CDCl3,ppm):δ 8.44 (d, 1H, J=4.2Hz), 7.63-7.60 (m, 2H), 7.52 (d, 1H, J=7.8Hz), 7.22-7.19 (m, 3H), 3.93 (s, 2H), 3.86 (s, 2H), 3.17 (t, 2H, J=7.2Hz), 3.13 (s, 3H), 3.09 (s, 3H), 2.77 (t, 2H, J=7.2Hz), 2.24 (s, 3H);ESI-MS:352.2(M+1)+;HRMS (ESI):Calculated value：C20H26N5O(M+H)+:352.2137;Measured value：352.2144.
Embodiment 25
Compound 25：3- (2- ((((1H- benzimidazolyl-2 radicals-yl) methyl) (methyl) amino) methyl) pyridin-3-yl)-N- (4- luorobenzyls) propionamide
Reaction process is identical with embodiment 23, only replaces cyclopropylamine with 4-Fluorobenzylamine, and it is white size to obtain title compound Shape thing (yield 34%).
1H NMR(300MHz,CDCl3,ppm):δ 8.43 (d, 1H, J=4.5Hz), 7.56-7.51 (m, 3H), 7.22- 7.15 (m, 5H), 6.97 (t, 2H, J=8.4Hz), 6.88 (brs, 1H), 4.46 (d, 2H, J=5.4Hz), 3.84 (s, 2H), 3.81 (s, 2H), 3.16 (t, 2H, J=7.8Hz), 2.68 (t, 2H, J=7.8Hz), 2.23 (s, 3H);EI-MS:431(M)+; HRMS(EI):Calculated value：C25H26FN5O(M)+:431.2121;Measured value：431.2121.
Embodiment 26
Compound 26：3- (2- ((((1H- benzimidazolyl-2 radicals-yl) methyl) (methyl) amino) methyl) pyridin-3-yl)-N, N- dimethylpropane -1- amine
Step a：(3- (3- aminopropyls) pyridine -2- bases) methanol
Under stirring, to 3- (2- (methylol) pyridin-3-yl) propionitrile（700mg, 4.32mmol）Saturation methanolic ammonia solution （10ml）Middle addition Raney's nickel（1.24g）, mixture be stirred at room temperature under a hydrogen atmosphere reaction 20 it is small when.Cross and filter out catalyst, Residue i.e. title compound (brown oil, 666mg, yield 93%) is obtained to be directly used in next step.
Step b：(3- (3- (dimethylamino) propyl group) pyridine -2- bases) methanol
(3- (3- aminopropyls) pyridine -2- bases) methanol (129mg, 0.78mmol) is dissolved in ethanol-acetic acid (6mL-4mL) Mixed solvent, add formaldehyde (616 μ L) and palladium carbon (51mg), 9h is stirred at room temperature in mixture under a hydrogen atmosphere.Filter palladium removing Carbon, it is pale yellow oil (137mg, yield 91%) that filtrate concentration column chromatography, which obtains title compound,.
1H NMR(300MHz,CDCl3,ppm):δ 8.39 (d, 1H, J=4.8Hz), 7.50 (d, 1H, J=7.5Hz), 7.18-7.14 (m, 1H), 5.16 (brs, 1H), 4.72 (s, 2H), 2.59 (t, 2H, J=7.2Hz), 2.33 (t, 2H, J= 7.2Hz),2.26(s,6H),1.86-1.76(m,2H).
Step c：3- (3- (dimethylamino) propyl group) -2- pyridine carboxaldehydes
Under stirring, to the dichloromethane of (3- (3- (dimethylamino) propyl group) pyridine -2- bases) methanol (53mg, 0.27mmol) Dess-Martin oxidants (139mg, 0.33mmol) are added in (3mL) solution, reaction 12h is stirred at room temperature in mixture.Instead After answering, saturated sodium bicarbonate solution, liquid separation are added, water layer is extracted twice with dichloromethane again, and organic phase merges, anhydrous sulphur Sour sodium drying, it is pale yellow oil (45mg, yield 85%) that filtering and concentrating column chromatography, which obtains title compound,.
1H NMR(300MHz,CDCl3,ppm):δ 10.11 (s, 1H), 8.63 (d, 1H, J=4.2Hz), 7.65 (d, 1H, J =7.8Hz), 7.39-7.35 (m, 1H), 3.04 (t, 2H, J=7.8Hz), 2.50 (t, 2H, J=7.8Hz), 2.34 (s, 6H), 1.86-1.76(m,2H).
Step d：2- (chloromethyl) -1H- benzimidazole -1- carboxylic acid tert-butyl esters
In 0 DEG C, to 2- (chloromethyl)-benzimidazole (224mg, 1.34mmol, 1eq), di-tert-butyl dicarbonate (587mg, 2.68mmol, 2eq) and dichloromethane (6mL) solution of triethylamine (372 μ L, 2.68mmol) in add catalytic amount 4- diformazans Reaction 2h is stirred at room temperature in aminopyridine, mixture.Ethyl acetate dilution is added, successively with saturated sodium bicarbonate solution and saturation Salt is washed, anhydrous sodium sulfate drying, filtering and concentrating, and gained crude product (yellow oil, yield 67%) is directly used in next step Reaction.
Step e：1- (1H- benzimidazolyl-2 radicals-yl)-N- methyl methylamines
Under 0 DEG C of stirring, 2- (chloromethyl) -1H- benzimidazole -1- carboxylics are added portionwise into methylethylolamine solution (6mL) Tert-butyl acrylate (533mg, 2mmol), finishes, 12h is stirred at room temperature in mixture.Mixture is diluted with water, is extracted with dichloromethane Three times, organic phase, anhydrous sodium sulfate drying are merged, filtering and concentrating, residue column chromatography obtains title compound (300mg, yield 93%) it is pale yellow oil.
1H NMR(300MHz,CDCl3,ppm):δ7.55-7.52(m,2H),7.22-7.19(m,2H),6.22(brs, 1H),4.04(s,2H),2.47(s,3H).
Step f：3- (2- ((((1H- benzimidazolyl-2 radicals-yl) methyl) (methyl) amino) methyl) pyridin-3-yl)-N, N- Dimethylpropane -1- amine
Under stirring, to 3- (3- (dimethylamino) propyl group) -2- pyridine carboxaldehydes (45mg, 0.23mmol) and 1- (1H- benzo miaows Azoles -2- bases)-N- methyl methylamine (57mg, 0.35mmol) 1,2- dichloroethanes (2mL) solution in add triacetoxy borohydride hydrogen Change sodium (100mg, 0.47mmol).Mixture is stirred at room temperature 12h, adds dichloromethane and water dilution, liquid separation, water mutually again with Dichloromethane is extracted twice, and merges organic phase, anhydrous sodium sulfate drying, it is colourless that filtering and concentrating column chromatography, which obtains title compound, Jelly (36mg, yield 54%)
1H NMR(300MHz,CDCl3,ppm):δ 8.41 (d, 1H, J=4.8Hz), 7.60-7.47 (m, 3H), 7.24- 7.15 (m, 4H), 3.91 (s, 2H), 3.66 (s, 2H), 2.74 (t, 2H, J=7.8Hz), 2.48 (t, 2H, J=6.0Hz), 2.37 (s,6H),2.30(s,3H),1.91-1.80(m,2H);EI-MS:337(M)+;HRMS(EI):Calculated value：C20H27N5(M)+: 337.2266;Measured value：337.2274.
Embodiment 27
Compound 27：N- (3- (2- ((((1H- benzimidazolyl-2 radicals-yl) methyl) (methyl) amino) methyl) pyridin-3-yl) Propyl group) acetamide
Reaction process is identical with 26 step f of embodiment, only with N- (3- (2- formylpyridine -3- bases) propyl group) acetamide generations For 3- (3- (dimethylamino) propyl group) -2- pyridine carboxaldehydes, it is colorless gum (yield 60%) to obtain title compound.
1H NMR(300MHz,CDCl3,ppm):δ8.43(dd,1H,J1=4.8Hz,J2=1.2Hz),7.61(q,2H), 7.51 (d, 1H, J=7.8Hz), 7.23-7.17 (m, 3H), 3.83 (s, 2H), 3.74 (s, 2H), 3.25 (q, 2H, J= 6.3Hz), 2.71 (t, 2H, J=7.8Hz), 2.32 (s, 3H), 1.99 (s, 3H), 1.89-1.80 (m, 2H);EI-MS:351(M )+;HRMS(EI):Calculated value：C20H25N5O(M)+:351.2059;Measured value：351.2059.
The building-up process of wherein N- (3- (2- formylpyridine -3- bases) propyl group) acetamide is as follows：
Step 1：N- (3- (2- (hydroxymethyl) pyridin-3-yl) propyl group) acetamide
Under stirring, to (3- (3- aminopropyls) pyridine -2- bases) methanol (56mg, 0.34mmol, with 26 step a) of embodiment 1mL methanol solutions in add aceticanhydride (34 μ L, 0.35mmol) and triethylamine (49 μ L, 0.35mmol), mixture is at room temperature Stir 24h.Reaction solution concentrates, and it is yellow oil (30mg, yield 43%) that residue column chromatography, which obtains title compound,.
1H NMR(300MHz,CDCl3,ppm):δ 8.42 (d, 1H, J=4.5Hz), 7.52 (d, 1H, J=7.5Hz), 7.21-7.17 (m, 1H), 5.80 (brs, 1H), 4.73 (s, 2H), 3.30 (q, 2H, J=6.9Hz), 2.98 (brs, 1H), 2.57 (t, 2H, J=7.8Hz), 1.97 (s, 3H), 1.86-1.76 (m, 2H)
Step 2：N- (3- (2- formylpyridine -3- bases) propyl group) acetamide
Under stirring, to the 2mL of N- (3- (2- (hydroxymethyl) pyridin-3-yl) propyl group) acetamide (30mg, 0.14mmol) Dess-Martin oxidants (73mg, 0.17mmol) are added in dichloromethane solution.12h is stirred at room temperature in mixture.Reaction After, saturated sodium bicarbonate solution, liquid separation are added, water is mutually extracted twice with dichloromethane again, merges organic phase, anhydrous slufuric acid Sodium is dried, filtering and concentrating, is obtained title compound and is directly used in reaction in next step for yellow oil (yield 96%).
Embodiment 28
Compound 28：N- (3- (2- ((((1H- benzimidazolyl-2 radicals-yl) methyl) (methyl) amino) methyl) pyridin-3-yl) Propyl group) -2- (4- fluorophenyls) acetamide
Reaction process is identical with 26 step f of embodiment, only with 2- (4- fluorophenyls)-N- (3- (2- formylpyridine -3- bases) Propyl group) acetamide replaces 3- (3- (dimethylamino) propyl group) -2- pyridine carboxaldehydes, and obtain title compound and consolidate for weak yellow foam shape Body (yield 66%).
1H NMR(300MHz,CDCl3,ppm):δ9.15(brs,1H),8.46(d,1H,J=4.2Hz),7.62-7.59(m, 2H), 7.50 (d, 1H, J=7.8Hz), 7.28-7.18 (m, 5H), 6.99 (t, 2H, J=8.4Hz), 6.86 (brs, 1H), 3.85 (s, 2H), 3.74 (s, 2H), 3.56 (s, 2H), 3.32-3.26 (m, 2H), 2.70 (t, 2H, J=7.5Hz), 1.891-1.80 (m,2H);EI-MS:445(M)+;HRMS(EI):Calculated value：C26H28FN5O(M)+:445.2278;Measured value：445.2286.
The building-up process of wherein 2- (4- fluorophenyls)-N- (3- (2- formylpyridine -3- bases) propyl group) acetamide is as follows：
Step 1：2- (4- fluorophenyls)-N- (3- (2- (hydroxymethyl) pyridin-3-yl) propyl group) acetamide
Under stirring, to (3- (3- aminopropyls) pyridine -2- bases) methanol (115mg, 0.69mmol, with 26 step of embodiment A) and 4- fluorophenylacetic acids (117mg, 0.76mmol) n,N-Dimethylformamide (3mL) solution in add benzotriazole- N, N, N', N'- tetramethylurea hexafluorophosphoric acid ester (272mg, 0.72mmol) and n,N-diisopropylethylamine (160 μ L, 0.97mmol).6h is stirred at room temperature in mixture, solvent is evaporated off, it is yellow oily that residue column chromatography, which obtains title compound, Thing (53mg, yield 25%).
1H NMR(300MHz,CDCl3,ppm):δ 8.38 (d, 1H, J=4.2Hz), 7.46 (d, 1H, J=7.5Hz), 7.26-7.14 (m, 3H), 7.02 (t, 2H, J=8.4Hz), 5.77 (brs, 1H), 4.65 (s, 2H), 4.30 (brs, 1H), 3.51 (s, 2H), 3.25 (q, 2H, J=6.6Hz), 2.48 (t, 2H, J=7.8Hz), 1.78-1.69 (m, 2H)
Step 2：2- (4- fluorophenyls)-N- (3- (2- formylpyridine -3- bases propyl group) acetamides
Building-up process step of the building-up process with N- in embodiment 27 (3- (2- formylpyridine -3- bases) propyl group) acetamide 2, N- (3- (2- (hydroxyl first is only replaced with 2- (4- fluorophenyls)-N- (3- (2- (hydroxymethyl) pyridin-3-yl) propyl group) acetamide Base) pyridin-3-yl) propyl group) acetamide, it is yellow oil (yield 98%) to obtain title compound.
Embodiment 29
Compound 29：N- (3- (2- ((((1H- benzimidazolyl-2 radicals-yl) methyl) (methyl) amino) methyl) pyridin-3-yl) Propyl group) Methanesulfomide
Reaction process is identical with 26 step f of embodiment, only with N- (3- (2- formylpyridine -3- bases) propyl group) Methanesulfomide Instead of 3- (3- (dimethylamino) propyl group) -2- pyridine carboxaldehydes, it is white gum thing (yield 55%) to obtain title compound.
1H NMR(300MHz,CDCl3,ppm):δ 8.52 (d, 1H, J=4.5Hz), 7.77 (brs, 1H), 7.68-7.66 (m, 2H), 7.59 (d, 1H, J=7.8Hz), 7.30-7.26 (m, 3H), 3.87 (s, 2H), 3.85 (s, 2H), 2.97-2.93 (m, 2H),2.45(s,3H),2.00-1.91(m,2H);EI-MS:387(M)+;HRMS(EI):Calculated value：C19H25N5O2S(M)+: 387.1729;Measured value：387.1726.
The building-up process of wherein N- (3- (2- formylpyridine -3- bases) propyl group) Methanesulfomide is as follows：
Step 1：N- (3- (2- (hydroxymethyl) pyridin-3-yl) propyl group) Methanesulfomide
Under 0 DEG C of stirring, to (3- (3- aminopropyls) pyridine -2- bases) methanol (32mg, 0.19mmol, with embodiment 1) Dichloromethane solution in add pyridine (15 μ L, 0.19mmol) and mesyl chloride (14 μ L, 0.19mmol).Mixture is in room temperature Under be stirred overnight.After completion of the reaction, dichloromethane dilution is added, is washed successively with being hydrated saturated common salt, organic phase anhydrous slufuric acid Sodium is dried, filtering and concentrating, and residue is directly used in for yellow oil (yield 38%) to react in next step.
Step 2：N- (3- (2- formylpyridine -3- bases) propyl group) Methanesulfomide
Building-up process step of the building-up process with N- in embodiment 27 (3- (2- formylpyridine -3- bases) propyl group) acetamide 2, N- (3- (2- (hydroxymethyl) pyridines -3- are only replaced with N- (3- (2- (hydroxymethyl) pyridin-3-yl) propyl group) Methanesulfomide Base) propyl group) acetamide, it is yellow oil (yield 98%) to obtain title compound.
Embodiment 30
Compound 30：3- (2- ((((1H- benzimidazolyl-2 radicals-yl) methyl) (methyl) amino) methyl) pyridin-3-yl) third The amidocarbonic acid tert-butyl ester
Reaction process is identical with 26 step f of embodiment, only with 3- (2- formylpyridine -3- bases) the tertiary fourth of propyl carbamic acid Ester replaces 3- (3- (dimethylamino) propyl group) -2- pyridine carboxaldehydes, and it is white gum thing (yield 58%) to obtain title compound.
1H NMR(300MHz,CDCl3,ppm):δ8.45-8.43(m,1H),7.59-7.51(m,3H),7.21-7.18(m, 3H),5.75(brs,1H),3.88(s,2H),3.79(s,2H),3.12-3.09(m,2H),2.73-2.77(m,2H),2.44 (s,3H),1.86-1.84(m,2H),1.46(s,9H);EI-MS:409(M)+
The building-up process of wherein 3- (2- formylpyridine -3- bases) propylcarbamate is as follows：
Step 1：3- (2- (hydroxymethyl) pyridin-3-yl) propylcarbamate
Under stirring, to the dichloro of (3- (3- aminopropyls) pyridine -2- bases) methanol (46mg, 0.28mmol, with embodiment 1) Di-tert-butyl dicarbonate ((Boc) is added in methane (2mL) solution2O) (66mg, 0.31mmol), mixture is stirred at room temperature 12h.After completion of the reaction, solvent is evaporated off, it is yellow oil (49mg, yield 67%) that residue column chromatography, which obtains title compound,.
1H NMR(300MHz,CDCl3,ppm):δ 8.41 (d, 1H, J=3.9Hz), 7.50 (d, 1H, J=7.2Hz), 7.20-7.16 (m, 1H), 4.72 (s, 2H), 4.65 (brs, 1H), 3.21-3.16 (m, 2H), 2.54 (t, 2H, J=7.8Hz), 1.82-1.72(m,2H),1.44(s,9H).
Step 2：3- (2- formylpyridine -3- bases) propylcarbamate
Building-up process step of the building-up process with N- in embodiment 27 (3- (2- formylpyridine -3- bases) propyl group) acetamide 2, only with 3- (2- (hydroxymethyl) pyridin-3-yl) propylcarbamate replace N- (3- (2- (hydroxymethyl) pyridine- 3- yls) propyl group) acetamide, it is yellow oil (yield 98%) to obtain title compound.
Embodiment 31
Compound 31：3- (2- ((((1H- benzimidazolyl-2 radicals-yl) methyl) (methyl) amino) methyl) pyridin-3-yl) third Alkane -1- amine
Under stirring, to 3- (2- ((((1H- benzimidazolyl-2 radicals-yl) methyl) (methyl) amino) methyl) pyridin-3-yl) third Trifluoroacetic acid (1mL) is added in dichloromethane (2mL) solution of the amidocarbonic acid tert-butyl ester (23mg, 0.056mmol), mixture exists 12h is stirred at room temperature.Solvent is evaporated off, it is white gum thing (13mg, yield 71%) that residue column chromatography, which obtains title compound,.
1H NMR(300MHz,CDCl3,ppm):δ8.45-8.43(m,1H),7.59-7.51(m,3H),7.21-7.18(m, 3H),3.88(s,2H),3.79(s,2H),2.88-2.80(m,4H),2.28(s,3H),1.91-1.81(m,2H);EI-MS: 309(M)+;HRMS(EI):Calculated value：C18H23N5(M)+:309.1953;Measured value：309.1954.
Embodiment 32
Compound 32：3- (3- (2- ((((1H- benzimidazolyl-2 radicals-yl) methyl) (methyl) amino) methyl) pyridin-3-yl) Propyl group) -1,1- dimethyl ureas
Reaction process is identical with 26 step f of embodiment, only with 3- (3- (2- formylpyridine -3- bases) propyl group) -1,1- bis- Methylurea replaces 3- (3- (dimethylamino) propyl group) -2- pyridine carboxaldehydes, and it is colorless gum (yield to obtain title compound 45%)。
1H NMR(300MHz,CDCl3,ppm):δ8.42(dd,1H,J1=4.8Hz,J2=1.2Hz), 7.62 (d, 2H, J= 3.0Hz),7.50(dd,1H,J1=7.8Hz,J2=1.8Hz), 7.21-7.14 (m, 3H), 4.86 (t, 1H, J=6.0Hz), 3.86 (s,2H),3.75(s,2H),3.28(dd,2H,J1=13.2Hz,J2=6.9Hz),2.89(s,6H),2.69(t,2H,J= 7.8Hz),2.29(s,3H),1.91-1.81(m,2H);EI-MS:380(M)+;HRMS(EI):Calculated value：C21H28N6O(M)+: 380.2325;Measured value：380.2317.
The building-up process of wherein 3- (3- (2- formylpyridine -3- bases) propyl group) -1,1- dimethyl ureas is as follows：
Step 1：3- (3- (2- (hydroxymethyl) pyridin-3-yl) propyl group) -1,1- dimethyl ureas
It is molten to the tetrahydrofuran of (3- (3- aminopropyls) pyridine -2- bases) methanol (30mg, 0.36mmol) under 0 DEG C of stirring N, N- wopropyl ethyl amines (23 μ L, 0.42mmol) and N, N- methyl amido formyl chloride (17 μ L, 0.38mmol) are added in liquid.Mixing 16h is stirred at room temperature in thing, solvent is evaporated off, residue is with water and dichloromethane liquid separation.Organic phase anhydrous sodium sulfate is dried, filtering Concentration, it is pale yellow oil (yield 76%) to obtain title compound, is directly used in and reacts in next step.
Step 2：3- (3- (2- formylpyridine -3- bases) propyl group) -1,1- dimethyl ureas
Building-up process step of the building-up process with N- in embodiment 27 (3- (2- formylpyridine -3- bases) propyl group) acetamide 2, N- (3- (2- formylpyridines -3- are only replaced with 3- (3- (2- (hydroxymethyl) pyridin-3-yl) propyl group) -1,1- dimethyl ureas Base) propyl group) acetamide, it is white gum thing (yield 98%) to obtain title compound.
Embodiment 33
Compound 33：2- ((((3- (3- (dimethylamino) propyl group) pyridine -2- bases) methyl) (methyl) amino) methyl) - 1H- benzimidazole -7- carboxylate methyl esters
Step a：N, N- methyl -3- (2- ((methylamino) methyl) pyridin-3-yl) propane -1- amine
To the methanol of 3- (3- (dimethylamino) propyl group) -2- pyridine carboxaldehydes (258mg, 1.34mmol, with embodiment 26) Methylethylolamine solution (485 μ L, 4.03mmol, 3eq) is added in (4mL) solution, mixture adds boron hydrogen after 2h is stirred at room temperature Change sodium (102mg, 2.69mmol, 2eq), mixture is stirred for 1h.After completion of the reaction, add water quenching go out reaction after methanol is evaporated off, Water mutually with after dichloromethane extraction three times, merges organic phase, anhydrous sodium sulfate drying, and filtering and concentrating, residue column chromatography obtains Title compound is yellow oil (yield 76%).
1H NMR(300MHz,CDCl3,ppm):δ 8.20 (d, 1H, J=3.9Hz), 7.27 (d, 1H, J=7.2Hz), 6.93- 6.89(m,1H),3.70(s,2H),3.38(s,1H),2.46(t,2H,J=7.8Hz),2.32(s,3H),2.11(t,2H,J= 7.2Hz),2.02(s,6H),1.60-1.50(m,2H).
Step b：2,3- diamino-methyl benzoates
2- amino -3- nitrobenzene methyls (2.5g, 12.75mmol) are dissolved in 20mL methanol, add palladium-carbon (500mg).24h is stirred at room temperature in mixture under a hydrogen atmosphere, and filtering removes palladium carbon, filtrate concentration, and residue column chromatography is marked It is brown solid to inscribe compound (2g, yield 95%).
1H-NMR(CDCl3):δ7.47(d,1H,J=8.4Hz),6.85(d,1H,J=7.8Hz),6.60(t,1H,J= 7.8Hz),5.56(brs,2H),3.87(s,3H),3.34(brs,2H).
Step c：2- (chloromethyl) -1H- benzimidazole -7- carboxylate methyl esters
By 2,3- diamino-methyl benzoates (53mg, 0.32mmol), monoxone (46mg, 0.48mmol), double (2- oxygen Generation -3- oxazoles alkyl) secondary phosphoryl chloride phosphorus oxychloride (90mg, 0.35mmol) and n,N-diisopropylethylamine (108 μ L, 0.64mmol) be dissolved in second Nitrile (3mL), 2h is stirred at room temperature in mixture.Gained crude product is dissolved in acetic acid (3mL) after reaction solution concentration, is stirred at 70 DEG C Reaction 2h to be mixed, is let cool, is concentrated, residue is diluted with dichloromethane and 2M methanolic ammonia solutions, is crossed and is filtered out insoluble matter, filtrate concentration, It is faint yellow solid (58mg, yield 82%) that residue column chromatography, which obtains title compound,.
1H-NMR(CDCl3):δ11.09(brs,1H),7.84(t,2H,J=7.8Hz),7.31(brs,1H),7.19(t, 1H,J=7.8Hz),6.87(brs,1H),5.15(s,2H),4.63(d,2H,J=6.0Hz),3.92(s,3H).
Step d：2- ((((3- (3- (dimethylamino) propyl group) pyridine -2- bases) methyl) (methyl) amino) methyl) -1H- Benzimidazole -7- carboxylate methyl esters
Under stirring, to 2- (chloromethyl) -1H- benzimidazole -7- carboxylate methyl esters (123mg, 0.55mmol) and N, N- diformazan In acetonitrile (8mL) solution of base -3- (2- ((methylamino) methyl) pyridin-3-yl) propane -1- amine (95mg, 0.46mmol) according to Secondary addition n,N-diisopropylethylamine (114 μ L, 0.69mmol) and potassium iodide (8mg, 0.046mmol).Mixture is at 60 DEG C Stirring reaction 12h, solvent evaporated, it is faint yellow jelly (yield 63%) that residue column chromatography, which obtains title compound,.
1H-NMR(CDCl3):δ12.87(brs,1H),8.64(d,1H,J=4.5Hz),7.96-7.92(m,2H),7.61 (d,1H,J=7.8Hz),7.30-7.24(m,2H),4.05(s,3H),3.84(s,4H),2.82(t,2H,J=7.8Hz),2.48 (s,3H),2.33(t,2H,J=7.5Hz),2.24(s,6H),1.87-1.77(m,2H);EI-MS:395(M+);HRMS(EI): Calculated value：C22H29N5O2(M)+:395.2313;Measured value：395.2321.
Embodiment 34
Compound 34：3- (2- ((((1H- benzimidazolyl-2 radicals-yl) methyl) (methyl) amino) methyl) phenyl) propionitrile
Step a：(E) -3- (2- Fonnylphenyls) acrylonitrile
2- bromobenzaldehydes (585 μ L, 5mmol) are dissolved in toluene (10mL), sequentially add palladium (24mg, 0.1mmol), three (o-tolyl) phosphine (61mg, 0.2mmol), acrylonitrile (494 μ L, 7.5mmol) and triethylamine (2.0mL).It is mixed Compound is refluxed 40h under nitrogen atmosphere.Let cool, diluted with water, dichloromethane is extracted twice, and merges organic phase, anhydrous slufuric acid Sodium is dried, and filtering and concentrating, it is yellow oil (466mg, yield 60%) that residue column chromatography, which obtains title compound,.
1H-NMR(CDCl3):δ10.13(s,1H),8.40(d,1H,J=16.5Hz),7.87-7.82(m,1H),7.67- 7.56(m,3H),5.85(d 1H,J=16.5Hz).
Step b：3- (2- (hydroxymethyl) phenyl) propionitrile
(E) -3- (2- Fonnylphenyls) acrylonitrile (466mg, 2.9mmol) is dissolved in methanol (10mL), adds palladium carbon (93mg).24h is stirred at room temperature in mixture under a hydrogen atmosphere.Filtering removes palladium carbon, filtrate concentration, and residue column chromatography obtains title Compound is pale yellow oil (477mg, yield 100%).
1H-NMR(CDCl3):δ7.34-7.23(m,4H),4.66(s,2H),3.03(t,2H,J=7.5Hz),2.67(t, 2H,J=7.5Hz),2.40(brs,1H).
Step c：3- (2- Fonnylphenyls) propionitrile
It is molten to the dichloromethane DCM (10mL) of 3- (2- (hydroxymethyl) phenyl) propionitrile (485mg, 3.0mmol) under stirring In liquid, Dess-Martin oxidants (1.40g, 3.3mmol) are added, 2h is stirred at room temperature in mixture under nitrogen atmosphere.React Finish, add dichloromethane dilution, washed successively with saturated sodium bicarbonate solution and saturated common salt, organic phase anhydrous sodium sulfate is done Dry, filtering and concentrating, residue is directly used in react in next step.
Step d：3- (2- ((methylamino) methyl) phenyl) propionitrile
Methylethylolamine is added into methanol (10mL) solution of 3- (2- Fonnylphenyls) propionitrile (712mg, 4.47mmol) Solution (895 μ L, 8.95mmol), mixture add sodium borohydride (1340mg, 8.95mmol), mixture after 2h is stirred at room temperature It is stirred for 1h.After completion of the reaction, add water quenching and go out and be evaporated off methanol after reaction, water mutually with after dichloromethane extraction three times, is associated with Machine phase, anhydrous sodium sulfate drying, filtering and concentrating, residue column chromatography obtains title compound, and for yellow oil, (154mg, is received Rate 62%).
1H-NMR(CDCl3):δ7.28-7.18(m,4H),3.71(s,2H),3.02(t,2H,J=7.5Hz),2.70(t, 2H,J=7.5Hz),2.44(s,3H),1.44(brs,1H).
Step e：2- (((2- (2- cyano group) benzyl) (methyl) amino) methyl) -1H- benzimidazole -1- carboxylic acid tert-butyl esters
Under stirring, to acetonitrile (5mL) solution of 3- (2- ((methylamino) methyl) phenyl) propionitrile (73mg, 0.42mmol) Middle addition N, N- wopropyl ethyl amines (104 μ L, 0.63mmol), 2- (chloromethyl) -1H- benzimidazole -1- carboxylic acid tert-butyl esters (134mg, 0.50mmol, with step h) in embodiment 1 and potassium iodide (7mg, 0.042mmol).Mixture under nitrogen atmosphere, in Stirring reaction 15h, lets cool at 60 DEG C, concentrates, and residue is with water and dichloromethane liquid separation, the drying of organic phase anhydrous sodium sulfate, mistake Filter concentration, residue column chromatography obtain title compound pale yellow oil (158mg, yield 82%).
1H-NMR(CDCl3):δ7.91-7.88(m,1H),7.78-7.74(m,1H),7.35-7.15(m,6H),4.16(s, 2H),2.98(t,2H,J=7.5Hz),2.63(t,2H,J=7.5Hz),2.31(s,3H),1.72(s,9H).
Step f：3- (2- ((((1H- benzimidazolyl-2 radicals-yl) methyl) (methyl) amino) methyl) phenyl) propionitrile
Under 0 DEG C of stirring, to 2- (((2- (2- cyano group) benzyl) (methyl) amino) methyl) -1H- benzimidazole -1- carboxylic acids Trifluoroacetic acid (2mL) is added in dichloromethane (5mL) solution of the tert-butyl ester (138mg, 0.34mmol), mixture stirs at room temperature Mix 2h.Solvent and remaining trifluoroacetic acid are spin-dried for, residue is neutralized with saturated sodium carbonate solution, and water mutually extracts three with dichloromethane After secondary, merge organic phase, anhydrous sodium sulfate drying, filtering and concentrating, it is pale yellow glue that residue column chromatography, which obtains title compound, Shape thing (80mg, yield 77%).
1H-NMR(CDCl3):δ7.77-7.74(m,2H),7.42-7.31(m,6H),4.01(s,2H),3.74(s,2H), 3.14(t,2H,J=7.5Hz),2.76(t,2H,J=7.5Hz),2.38(s,3H);EI-MS:305(M+H)+;HRMS(EI):Meter Calculation value：C19H21N4(M+H)+:305.1766;Measured value：305.1767.
Embodiment 35
Compound 35：(E) -3- (2- ((((1- benzyls -1H- benzimidazolyl-2 radicals-yl) methyl) (methyl) amino) methyl) benzene Base) acrylonitrile
Compound 36：(Z) -3- (2- ((((1- benzyls -1H- benzimidazolyl-2 radicals-yl) methyl) (methyl) amino) methyl) benzene Base) acrylonitrile
Step a：1- (2- bromophenyls)-N- methyl methylamines
Reaction process only replaces 3- (2- formylpyridine -3- bases) propionitrile with step g in embodiment 1 with 2- bromobenzaldehydes, It is yellow oil (yield 96%) to obtain title compound.
1H NMR(300MHz,CDCl3,ppm):1H NMR(300MHz,CDCl3,ppm):δ 7.52 (d, 1H, J= 7.8Hz),7.34(dd,1H,J1=7.2Hz,J2=1.5Hz),7.28-7.23(m,1H),7.09(td,J1=7.8Hz,J2= 1.5Hz),3.80(s,2H),2.43(s,3H),1.83(s,1H).
Step b：2- (((2- bromobenzyls) (methyl) amino) methyl) -1H- benzimidazole -1- carboxylic acid tert-butyl esters
Reaction process only replaces 3- (2- ((methyl ammonia with step i in embodiment 1 with 1- (2- bromophenyls)-N- methyl methylamine Base) methyl) pyridin-3-yl) propionitrile, it is yellow jelly (yield 75%) to obtain title compound.
1H NMR(300MHz,CDCl3,ppm):δ7.91-7.88(m,1H),7.79-7.76(m,1H),7.55-7.47(m, 2H), 7.35-7.32 (m, 2H), 7.23 (t, 1H, J=7.5Hz), 7.05 (t, 1H, J=7.5Hz), 4.24 (s, 2H), 3.84 (s,2H),2.44(s,3H),1.72(s,9H).
Step c：N- ((1H- benzimidazolyl-2 radicals-yl) methyl) -1- (2- bromophenyls)-N- methyl methylamines
Reaction process is with embodiment 2, only with 2- (((2- bromobenzyls) (methyl) amino) methyl) -1H- benzimidazole -1- carboxylics Tert-butyl acrylate replaces 3- (2- cyano ethyls) pyridine -2- bases) methyl) (methyl) amino) methyl) -1H- benzimidazole -1- carboxylic acids The tert-butyl ester, it is yellow solid (yield 93%) to obtain title compound.
Step d：1- (1- benzyls -1H- benzimidazolyl-2 radicals-yl)-N- (2- bromobenzyls)-N- methyl methylamines
0 DEG C stirring under, to N- ((1H- benzimidazolyl-2 radicals-yl) methyl) -1- (2- bromophenyls)-N- methyl methylamine (448mg, In DMF (5mL) solution 1.36mmol), sodium hydrogen (36mg, 1.50mmol) is added, mixture stirs 1h at such a temperature.Add Bromobenzyl (175 μ L, 1.47mmol), mixture continues that 24h is stirred at room temperature.Solvent evaporated, residue is with water and dichloromethane Liquid separation.Organic layer anhydrous sodium sulfate is dried, and filtering and concentrating, it is yellow oil that residue column chromatography, which obtains title compound, (563mg, yield 99%).
1H NMR(300MHz,CDCl3,ppm):δ 7.91 (d, 1H, J=7.2Hz), 7.65 (d, 1H, J=8.1Hz), 7.38-7.18(m,9H),7.04(brs,2H),5.66(s,2H),3.97(s,2H),3.81(s,2H),2.40(s,3H).
Step e：(E) -3- (2- ((((1- benzyls -1H- benzimidazolyl-2 radicals-yl) methyl) (methyl) amino) methyl) phenyl) Acrylonitrile
(Z) -3- (2- ((((1- benzyls -1H- benzimidazolyl-2 radicals-yl) methyl) (methyl) amino) methyl) phenyl) acrylonitrile
By 1- (1- benzyls -1H- benzimidazolyl-2 radicals-yl)-N- (2- bromobenzyls)-N- methyl methylamine (409mg, 0.98mmol), acrylonitrile (645 μ L, 9.8mmol), palladium (48mg, 0.196mmol), tri-o-tolyl phosphine (298mg, 0.98mmol) it is dissolved in triethylamine (681 μ L, 4.9mmol) in 2mL DMF, mixture reacts 19h in 110 DEG C under nitrogen atmosphere. Let cool, solvent is evaporated off, residue is with water and dichloromethane liquid separation.Organic layer anhydrous sodium sulfate is dried, and is filtered, concentration.Residue It is respectively that faint yellow jelly (trans, 288mg, yield 75%) and yellow powdery solid are (suitable that column chromatography, which obtains title compound, Formula, 58mg, yield 15%).
1H NMR(300MHz,CDCl3,ppm):δ 7.79 (d, 1H, J=8.1Hz), 7.73 (d, 1H, J=17.1Hz), 7.47 (d, 1H, J=6.9Hz), 7.32-7.25 (m, 9H), 6.90 (brs, 2H), 5.74 (d, 1H, J=17.1Hz), 5.47 (s, 2H),3.78(s,2H),3.63(s,2H),2.26(s,3H).
1H NMR(300MHz,CDCl3,ppm):δ 7.98 (d, 1H, J=7.8Hz), 7.77 (d, 1H, J=7.8Hz), 7.37-7.16 (m, 10H), 6.86 (brs, 2H), 5.26 (s, 2H), 5.11 (d, 1H, J=12Hz), 3.73 (s, 2H), 3.61 (s,2H),2.32(s,3H).
Embodiment 36
Compound 37：3- (2- ((((1- benzyls -1H- benzimidazolyl-2 radicals-yl) methyl) (methyl) amino) methyl) phenyl) Propionitrile
Compound 35 (87mg, 0.22mmol) is dissolved in methanol (5mL), adds palladium carbon (43mg).Mixture is in nitrogen atmosphere Under 24h is stirred at room temperature.Catalyst, filtrate concentration are filtered out, residue column chromatography obtains title compound (56mg, yield 64%) For colorless gum.
1H NMR(300MHz,CDCl3,ppm):δ 7.79 (d, 1H, J=6.9Hz), 7.25-7.18 (m, 10H), 6.90 (brs, 2H), 5.35 (s, 2H), 3.78 (s, 2H), 3.60 (s, 2H), 2.91 (t, 2H, J=7.5Hz), 2.49 (t, 2H, J= 7.5Hz),2.29(s,3H).
Embodiment 37
Compound 38：1- (7- (4- methylpiperazine-1-yls) -3H- imidazoles [4,5-b] pyridine -2- bases)-N- ((3- methyl pyrroles Pyridine -2- bases) methyl) methylamine
Compound 39：N- methyl isophthalic acids-(7- (4- methylpiperazine-1-yls) -3H- imidazoles [4,5-b] pyridine -2- bases)-N- ((3- picoline -2- bases) methyl) methylamine
Step 1：2- amino -3- nitro -4- chloropyridines
Under 0 DEG C of stirring, into the concentrated sulfuric acid solution (40.8mL) of 2- amino -4- chloropyridines (5.00g, 0.0389mol) Concentrated nitric acid (5.00g, 0.0389mol) and the concentrated sulfuric acid (3.89g, 0.0389mol) is added dropwise, finishes, mixture rises to naturally 1h is stirred at room temperature.Then reaction solution is poured into the mixture of 200g ice and 100mL water, separates out a large amount of yellow solids, filtering is received Collect these solids.It is 9 that filtrate is neutralized to PH with 28% ammonium hydroxide, then is extracted with ethyl acetate three times, collects organic phase.Filter To solid also be soluble in ethyl acetate, and with ammonium hydroxide tune PH to 9, the organic phase isolated merges with foregoing organic phase, anhydrous sulphur Sour sodium drying, concentration, it is yellow solid that residue column chromatography, which obtains title compound (2.233g, yield 33%),.
1H NMR(300MHz,CDCl3,ppm):δ6.01(brs,2H),6.81(d,1H,J=5.1Hz),8.09(d,1H,J= 5.1Hz);EI-MS:173(M+)。
Step 2：4- (4- methylpiperazine-1-yls) -3- nitropyridine -2- amine
2- amino -3- nitro -4- chloropyridines (967mg, 5.59mmol) are dissolved in isopropanol (20mL), add DIPEA (1.85mL, 11.18mmol), then adds N methyl piperazine (0.744mL, 6.71mmol).Mixture reacts at 90 DEG C 12h, lets cool and separates out a large amount of bright yellow solids, and filtering, is washed with isopropanol and ether successively, and vacuum drying obtains title compound (1.21g, yield 92%) is bright yellow solid.
1H NMR(300MHz,CDCl3,ppm):δ2.34(s,3H),2.515(t,4H,J=4.8Hz),3.23(t,4H,J= 4.8Hz),6.12(s,2H),6.20(d,1H,J=6.0Hz),7.83(d,1H,J=5.4Hz)。
Step 3：4- (4- methylpiperazine-1-yls) pyridine -2,3- diamines
4- (4- methylpiperazine-1-yls) -3- nitropyridine -2- amine (1.21g, 5.1mmol) is dissolved in methanol (50mL), is added Enter Pd-C (242mg), mixture reacts 12h under room temperature hydrogen atmosphere.Pd-C is filtered out, column chromatography obtains title after filtrate concentration Compound (1.064g, yield 100%) is light yellow solid.
1H NMR(300MHz,CDCl3,ppm):δ2.29(s,3H),2.51(s,4H),2.90(s,4H)4.20(brs, 4H),6.41(d,1H,J=5.1Hz),7.51(d,1H,J=5.4Hz);EI-MS:207(M+)。
Step 4：(7- (4- methylpiperazine-1-yls) -1H- imidazoles [4,5-b] pyridine -2- bases) methyl carbamic acid benzyl ester
The glycine (554mg, 2.65mmol) and 4- (4- methylpiperazine-1-yls) pyridine -2,3- diamines that Cbz is protected (497mg, 2.4mmol) is dissolved in DMF (26mL).Add benzotriazole-N, N, N', N'- tetramethylurea hexafluorophosphate (HBTU, 948mg, 2.50mmol) and diisopropylethylamine (DIPEA, 555 μ L, 3.36mmol), mixture stirs at 50 DEG C 24h.A large amount of white solids are separated out, let cool filtering, filter cake is washed with water, vacuum drying obtains title compound (499mg, yield 55%) it is white solid.
1H NMR(300MHz,CDCl3,ppm):δ2.36(s,3H),2.60(t,4H,J=4.8Hz),3.91(s,4H), 4.62(d,2H,J=5.7Hz),5.14(s,1H),5.16(s,2H),5.71(brs,1H)6.38(d,1H,J=6.3Hz),7.35 (d,5H,J=2.1Hz),8.04(d,1H,J=6.0Hz);ESI-MS:381.2(M+H)+
Step 5：(7- (4- methylpiperazine-1-yls) -1H- imidazoles [4,5-b] pyridine -2- bases) methylamine
By (7- (4- methylpiperazine-1-yls) -1H- imidazoles [4,5-b] pyridine -2- bases) methyl carbamic acid benzyl ester (773mg, 2.03mmol) is dissolved in the mixed liquor of methanol (15mL) and acetic acid (5mL), adds Pd-C (155mg), mixture is in room 12h is stirred under warm hydrogen atmosphere, filters out Pd-C, column chromatography obtains title compound (344mg, yield 69%) and is after filtrate concentration Light yellow solid.
1H NMR(300MHz,CDCl3,ppm):δ2.38(s,3H),2.68(t,4H,J=4.8Hz),3.92(s,4H), 4.14(s,2H),6.36(d,1H,J=6.0Hz),7.85(d,1H,J=6.0Hz);ESI-MS:247(M+H)+
Step 6：1- (7- (4- methylpiperazine-1-yls) -3H- imidazoles [4,5-b] pyridine -2- bases)-N- ((3- picolines - 2- yls) methyl) methylamine
(7- (4- methylpiperazine-1-yls) -1H- imidazoles [4,5-b] pyridine -2- bases) methylamine (50mg, 0.2mmol) is dissolved in 2mLDCE (1,2- dichloroethanes), addition 3- methyl -2- pyridine carboxaldehydes (0.2mmol, 24mg) and NaBH (OAc) 3 (64mg, 0.3mmol), 2h is stirred at room temperature in mixture, is diluted with DCM, is washed with saturated sodium bicarbonate and saturated common salt, organic layer without Aqueous sodium persulfate is dried, and filtering and concentrating, it is faint yellow jelly (yield 46%) that residue column chromatography, which obtains title compound,.
1H NMR(300MHz,CDCl3,ppm):δ2.18(s,3H),2.34(s,3H),2.60(t,4H,J=5.1Hz), 3.90(t,4H,J=5.1Hz),3.95(s,2H),4.17(s,2H),6.32(d,1H,J=5.7Hz)7.09-7.05(m,1H), 7.38(dd,1H,J1=7.5Hz,J2=0.9Hz),8.01(d,1H,J=6.0Hz)8.40(dd,1H,J1=4.8Hz,J2= 0.9Hz);EI-MS:351(M+)
Step 7:N- methyl isophthalic acids-(7- (4- methylpiperazine-1-yls) -3H- imidazoles [4,5-b] pyridine -2- bases)-N- ((3- first Yl pyridines -2- bases) methyl) methylamine
By 1- (7- (4- methylpiperazine-1-yls) -3H- imidazoles [4,5-b] pyridine -2- bases)-N- ((3- picolines -2- Base) methyl) methylamine (0.1mmol, 35mg) is dissolved in 1mL DCE, add 37% formaldehyde (9.0 μ L, 0.12mmol) and NaBH (OAc) 3 (33mg, 0.15mmol), 2h is stirred at room temperature in mixture.Diluted, washed with saturated sodium bicarbonate and salt, organic layer with DCM Dried with anhydrous sodium sulfate, filtering and concentrating, it is faint yellow jelly (yield 61%) that residue column chromatography, which obtains title compound,.
1H NMR(300MHz,CDCl3,ppm):δ8.49(d,1H,J=4.8Hz),8.02(d,1H,J=5.7Hz),7.48 (d,1H,J=7.8Hz),7.17-7.13(m,1H),6.40(d,1H,J=5.7Hz),3.91(s,4H),3.83(s,2H),3.76 (s,2H),2.62(t,4H,J=5.1Hz),2.42(s,3H),2.39(s,3H),2.36(s,3H);13C NMR(100MHz, CDCl3,ppm):δ155.8,149.3,148.6,147.2,146.2,143.8,138.4,133.0,124.7,122.6, 101.8,59.3,54.5,54.2,47.2,45.7,43.2,18.2;EI-MS:365(M+);HRMS(EI):Calculated value： C20H27N7:365.2328;Measured value：365.2329.
Embodiment 38
Compound 40：N1- ((7- (4- methylpiperazine-1-yls) -3H- imidazoles [4,5-b] pyridine -2- bases) methyl)-N1- ((3- picoline -2- bases) methyl) butane -1,4- diamines
Step 1：2- amino -3- nitro -4- chloropyridines
Under 0 DEG C of stirring, into the concentrated sulfuric acid solution (40.8mL) of 2- amino -4- chloropyridines (5.00g, 0.0389mol) Concentrated nitric acid (5.00g, 0.0389mol) and the concentrated sulfuric acid (3.89g, 0.0389mol) is added dropwise, finishes, mixture rises to naturally 1h is stirred at room temperature.Then reaction solution is poured into the mixture of 200g ice and 100mL water, separates out a large amount of yellow solids, filtering is received Collect these solids.It is 9 that filtrate is neutralized to PH with 28% ammonium hydroxide, then is extracted with ethyl acetate three times, collects organic phase.Filter To solid also be soluble in ethyl acetate, and with ammonium hydroxide tune PH to 9, the organic phase isolated merges with foregoing organic phase, anhydrous sulphur Sour sodium drying, concentration, it is yellow solid that column chromatography, which obtains title compound (2.233g, yield 33%),.
1H NMR(300MHz,CDCl3,ppm):δ6.01(brs,2H),6.81(d,1H,J=5.1Hz),8.09(d,1H,J= 5.1Hz);EI-MS:173(M+)。
Step 2：4- (4- methylpiperazine-1-yls) -3- nitropyridine -2- amine
2- amino -3- nitro -4- chloropyridines (967mg, 5.59mmol) are dissolved in isopropanol (20mL), add DIPEA (1.85mL, 11.18mmol), then adds N methyl piperazine (0.744mL, 6.71mmol).Mixture reacts at 90 DEG C 12h, lets cool and separates out a large amount of bright yellow solids, and filtering, is washed with isopropanol and ether successively, and vacuum drying obtains title compound (1.21g, yield 92%) is bright yellow solid.
1H NMR(300MHz,CDCl3,ppm):δ2.34(s,3H),2.515(t,4H,J=4.8Hz),3.23(t,4H,J= 4.8Hz),6.12(s,2H),6.20(d,1H,J=6.0Hz),7.83(d,1H,J=5.4Hz)。
Step 3：4- (4- methylpiperazine-1-yls) pyridine -2,3- diamines
4- (4- methylpiperazine-1-yls) -3- nitropyridine -2- amine (1.21g, 5.1mmol) is dissolved in methanol (50mL), is added Enter Pd-C (242mg), mixture reacts 12h under room temperature hydrogen atmosphere.Pd-C is filtered out, column chromatography obtains title after filtrate concentration Compound (1.064g, yield 100%) is light yellow solid.
1H NMR(300MHz,CDCl3,ppm):δ2.29(s,3H),2.51(s,4H),2.90(s,4H)4.20(brs, 4H),6.41(d,1H,J=5.1Hz),7.51(d,1H,J=5.4Hz);EI-MS:207(M+)。
Step 4：(7- (4- methylpiperazine-1-yls) -1H- imidazoles [4,5-b] pyridine -2- bases) methyl carbamic acid benzyl ester
The glycine (554mg, 2.65mmol) and 4- (4- methylpiperazine-1-yls) pyridine -2,3- diamines that Cbz is protected (497mg, 2.4mmol) is dissolved in DMF (26mL).Add HBTU (948mg, 2.50mmol) and DIPEA (555 μ L, 3.36mmol), mixture stirs 24h at 50 DEG C.A large amount of white solids are separated out, let cool filtering, filter cake is washed with water, are dried in vacuo It is white solid to obtain title compound (499mg, yield 55%).
1H NMR(300MHz,CDCl3,ppm):δ2.36(s,3H),2.60(t,4H,J=4.8Hz),3.91(s,4H), 4.62(d,2H,J=5.7Hz),5.14(s,1H),5.16(s,2H),5.71(brs,1H)6.38(d,1H,J=6.3Hz),7.35 (d,5H,J=2.1Hz),8.04(d,1H,J=6.0Hz);ESI-MS:381.2(M+H)+
Step 5：(7- (4- methylpiperazine-1-yls) -1H- imidazoles [4,5-b] pyridine -2- bases) methylamine
By (7- (4- methylpiperazine-1-yls) -1H- imidazoles [4,5-b] pyridine -2- bases) methyl carbamic acid benzyl ester (773mg, 2.03mmol) is dissolved in the mixed liquor of methanol (15mL) and acetic acid (5mL), adds Pd-C (155mg), mixture is in room 12h is stirred under warm hydrogen atmosphere, filters out Pd-C, column chromatography obtains title compound (344mg, yield 69%) and is after filtrate concentration Light yellow solid.
1H NMR(300MHz,CDCl3,ppm):δ2.38(s,3H),2.68(t,4H,J=4.8Hz),3.92(s,4H), 4.14(s,2H),6.36(d,1H,J=6.0Hz),7.85(d,1H,J=6.0Hz);ESI-MS:247(M+H)+
Step 6：2- (4- ((7- (4- methylpiperazine-1-yls) -3H- imidazoles [4,5-b] pyridine -2- bases) methylamino) butyl) Iso-indoles -1,3- diketone
(7- (4- methylpiperazine-1-yls) -1H- imidazoles [4,5-b] pyridine -2- bases) methylamine (43mg, 0.175mmol) is molten In DMF (2mL), NaHCO is added3(29mg, 0.35mmol), add 2- (4- brombutyls) iso-indoles -1,3- diketone (74mg, 0.262mmol), 24h is stirred at room temperature in mixture.Remove DMF under reduced pressure, after residue diluted with water, extracted with dichloromethane Three times, anhydrous sodium sulfate is dried after organic layer is washed with saturated common salt.Filtering and concentrating, obtains title compound after residue column chromatography Thing is white solid (30mg, yield 38%).
1H NMR(300MHz,CDCl3,ppm):δ1.53-1.62(m,2H),1.68-1.77(m,2H),2.35(s,3H), 2.60(t,4H,J=4.5Hz),2.75(t,2H,J=6.9Hz),3.68(t,2H,J=6.9Hz),3.92(t,4H,J=4.5Hz), 4.07(s,2H),6.42(d,1H,J=5.7Hz),7.67-7.69(m,2H),7.79-7.82(m,2H),8.05(d,1H,J= 5.7Hz).
Step 7：2- (4- (((7- (4- methylpiperazine-1-yls) -3H- imidazoles [4,5-b] pyridine -2- bases) methyl) ((3- first Yl pyridines -2- bases) methyl) amino) butyl) iso-indoles -1,3- diketone
By 2- (4- ((7- (4- methylpiperazine-1-yls) -3H- imidazoles [4,5-b] pyridine -2- bases) methylamino) butyl) different Yin Diindyl -1,3- diketone (50mg, 0.112mmol) and 3- methyl -2- pyridine carboxaldehydes (16mg, 0.134mmol) are dissolved in DCE (2mL), add Enter sodium triacetoxy borohydride (36mg, 0.168mmol), 2h is stirred at room temperature in mixture.After being diluted with DCM, use successively Saturated sodium bicarbonate and saturated common salt washing, filtering and concentrating after organic layer is dried with anhydrous sodium sulfate, residue column chromatography obtain Title compound is faint yellow solid (42mg, yield 69%).
1H NMR(300MHz,CDCl3,ppm):δ1.58-1.72(m,4H),2.35(s,3H),2.39(s,3H),2.60- 2.64(m,6H),3.64(t,2H,J=6.9Hz),3.79(s,4H),3.883(t,4H,J=4.5Hz),6.40(d,1H,J= 5.4Hz),7.13-7.17(m,1H),7.48(d,1H,J=7.8Hz),7.69(q,2H,J=2.7Hz),7.82(q,2H,J= 2.7Hz),8.03(d,1H,J=5.4Hz)8.52(d,1H,J=4.2Hz).
Step 8：N1- ((7- (4- methylpiperazine-1-yls) -3H- imidazoles [4,5-b] pyridine -2- bases) methyl)-N1- ((3- first Yl pyridines -2- bases) methyl) butane -1,4- diamines
By 2- (4- (((7- (4- methylpiperazine-1-yls) -3H- imidazoles [4,5-b] pyridine -2- bases) methyl) ((3- methyl pyrroles Pyridine -2- bases) methyl) amino) butyl) iso-indoles -1,3- diketone (46mg, 0.083mmol) is dissolved in ethanol (2mL), add hydration Hydrazine (47 μ L, 0.83mmol), mixture reflux 2h, cold filtration, filtrate concentration after column chromatography obtain title compound (27mg, Yield 77%) it is faint yellow jelly.
1H NMR(300MHz,CDCl3,ppm):δ8.48(d,1H,J=4.2Hz),7.97(d,1H,J=6.0Hz),7.44 (d,1H,J=7.5Hz),7.13-7.09(m,1H),6.37(d,1H,J=5.7Hz),5.41(brs,2H),3.89(t,4H,J= 4.5Hz),3.81(s,2H),3.80(s,2H),2.73(t,2H,J=6.6Hz),2.60-2.57(m,6H),2.36(s,3H), 2.34(s,3H),1.68-1.59(m,2H),1.56-1.47(m,2H);13C NMR(100MHz,CDCl3,ppm):δ155.8, 149.5,147.4,146.0,144.2,138.5,138.3,132.1,122.5,122.2,101.3,57.1,54.6,50.2, 47.4,45.9,39.4,29.6,26.0,25.2,18.4;EI-MS:422(M)+;HRMS(EI):Calculated value：C23H34N8: 422.2906;Measured value：422.2910.
Embodiment 39
Compound 41：N- methyl-N- ((7- (4- methylpiperazine-1-yls) -3H- imidazoles [4,5-b] pyridine -2- bases) first Base) -5,6,7,8- tetrahydroquinoline -8- amine
Reaction process is identical with embodiment 37, only in step 6 with 6,7- dihydroquinoline -8 (5H) -one replace 3- methyl - 2- pyridine carboxaldehydes, it is yellow jelly to obtain compound 41.
1H NMR(300MHz,CDCl3,ppm):δ8.60(d,1H,J=4.5Hz),8.03(d,1H,J=6.3Hz),7.41 (d,1H,J=9.0Hz),7.15-7.10(m,1H),6.40(d,1H,J=5.4Hz),4.08-3.93(m,1H),4.02(s,2H), 3.87(s,4H),2.89-2.67(m,2H),2.61(t,4H,J=4.8Hz),2.35(s,3H),2.34(s,3H),2.07-1.89 (m,3H),1.77-1.68(m,1H);13C NMR(100MHz,CDCl3,ppm):δ156.6,151.5,149.3,147.3, 146.9,144.0,137.3,134.2,125.2,122.1,101.9,62.1,54.7,52.7,47.6,46.0,37.8,28.9, 22.9,20.6;EI-MS:391(M+);HRMS(EI):Calculated value：C22H29N7:391.2484;Measured value：391.2482.
Embodiment 40
Compound 42：N- methyl isophthalic acids-(7- (4- methylpiperazine-1-yls) -3H- imidazoles [4,5-b] pyridine -2- bases)-N- (pyrroles Pyridine -2- ylmethyls) methylamine
Reaction process is identical with embodiment 37, and 3- methyl -2- pyridine carboxaldehydes are replaced with 2- pyridine carboxaldehydes only in step 6, It is white gum thing to obtain compound 42.
Compound 42：1H NMR(300MHz,CDCl3,ppm):δ8.63(d,1H,J=5.1Hz),8.05(d,1H,J= 5.7Hz),7.63(td,1H,J1=7.8Hz,J2=1.8Hz),7.39(d,1H,J=7.8Hz),7.22-7.18(m,1H),6.41 (d,1H,J=5.7Hz),3.94-3.90(m,6H),3.78(s,2H),2.62(t,4H,J=5.1Hz),2.42(s,3H),2.36 (s,3H);EI-MS:351(M+);HRMS(EI):Calculated value：C19H25N7:351.2171;Measured value：351.2175.
Embodiment 41
Compound 43：N1- ((3H- imidazoles [4,5-b] pyridine -2- bases) methyl)-N1- ((3- picoline -2- bases) methyl) Butane -1,4- diamines
Step a：2- (2-aminopyridine -3- bases amino) -2- oxoethylamino benzyl formates
Under stirring, to Cbz protect glycine (1.80g, 8.6mmol) and 2,3- diamino-pyridine (894mg, Added in DMF (20mL) solution 8.19mmol) benzotriazole-N, N, N', N'- tetramethylurea hexafluorophosphate (3.728g, 9.83mmol) and diisopropylethylamine (2.707mL, 16.38mmol).Mixture stirs reaction 24h at 40 DEG C.Reaction solution is dense Contracting, is diluted with dichloromethane, is washed successively with saturated sodium bicarbonate solution and saturated common salt, the drying of organic phase anhydrous sodium sulfate, Filtering and concentrating, it is faint yellow solid (yield 75%) that residue column chromatography, which obtains title compound,.
1H NMR(300MHz,CD3OD,ppm):δ8.46(s,1H),7.78(d,1H,J=5.1Hz),7.44(d,1H,J= 6.3Hz),7.28(s,4H),6.56-6.51(m,1H),6.22(s,1H),5.06(s,2H),3.92(d,2H,J=5.1Hz), 3.70(brs,2H).
Step b：(3H- imidazoles [4,5-b] pyridine -2- bases) methyl carbamic acid benzyl ester
2- (2-aminopyridine -3- bases amino) -2- oxoethylaminos benzyl formate (1.138g) is dissolved in acetic acid (32mL) mixture is refluxed reaction 8h, lets cool concentration, residue column chromatography obtains title compound (525mg, yield 50%) For white solid.
Step c：(3H- imidazoles [4,5-b] pyridine -2- bases) methylamine
(3H- imidazoles [4,5-b] pyridine -2- bases) methyl carbamic acid benzyl ester (318mg, 1.12mmol) is dissolved in 4N brominations Acetate hydrogen solution (12.5mL), 1.5h is stirred at room temperature in mixture.Mixture concentration residue column chromatography obtains title compound Thing is white powdery solids (yield 75%).
1H NMR(300MHz,CD3OD,ppm):δ8.31-8.29(m,1H),7.95-7.92(m,1H),7.27-7.22(m, 1H),4.16(s,2H).
Step d：2- (4- ((3H- imidazoles [4,5-b] pyridine -2- bases) methylamino) butyl) isoindoline -1,3- two Ketone
It is molten to the 3mL DMF of (3H- imidazoles [4,5-b] pyridine -2- bases) methylamine (56mg, 0.378mmol, 1eq) under stirring In liquid, addition sodium acid carbonate (63mg, 0.756mmol), 2- (4- brombutyls) iso-indoles -1,3- diketone (159mg, 0.566mmol), 24h is stirred at room temperature in mixture.Reaction solution concentrates, and residue is diluted with water, and three are extracted with dichloromethane It is secondary.Merge organic phase, anhydrous sodium sulfate drying, filtering and concentrating, it is colorless gum that residue column chromatography, which obtains title compound, (40mg, yield 30%).
1H NMR(300MHz,CDCl3,ppm):δ8.37(dd,1H,J1=4.8Hz,J2=1.5Hz),7.93(dd,1H,J1= 7.8Hz,J2=1.5Hz),7.81-7.78(m,2H),7.69-7.66(m,2H),7.20-7.15(m,1H),4.18(s,2H), 3.67(t,2H,J=6.9Hz),2.76(t,2H,J=6.9Hz),1.78-1.68(m,2H),1.63-1.53(m,2H).
Step e：2- (4- (((3H- imidazoles [4,5-b] pyridine -2- bases) methyl) ((3- picoline -2- bases) methyl) ammonia Base) butyl) isoindoline -1,3- diketone
Under stirring, to 2- (4- ((3H- imidazoles [4,5-b] pyridine -2- bases) methylamino) butyl) isoindoline -1,3- Added in 1,2- dichloroethanes (2mL) solution of diketone (40mg, 0.114mmol) 3- methyl -2- pyridine carboxaldehydes (17mg, 0.137mmol) and sodium triacetoxy borohydride (37mg, 0.172mmol).2h is stirred at room temperature in mixture, with dichloromethane Alkane dilutes, and is washed successively with saturated sodium bicarbonate solution and saturated common salt, the drying of organic phase anhydrous sodium sulfate, and filtering and concentrating is residual It is colorless gum (yield 94%) that excess column chromatography, which obtains title compound,.
Step f：N1- ((3H- imidazoles [4,5-b] pyridine -2- bases) methyl)-N1- ((3- picoline -2- bases) methyl) fourth Alkane -1,4- diamines
Under stirring, to 2- (4- (((3H- imidazoles [4,5-b] pyridine -2- bases) methyl) ((3- picoline -2- bases) methyl) Amino) butyl) isoindoline -1,3- diketone (49mg, 0.108mmol) ethanol (2mL) solution in, add hydrazine hydrate (49 μ L, 0.862mmol), mixture is refluxed 2h, lets cool, filtering, and filtrate concentration, residue column chromatography obtains title compound and is Colorless gum (yield 71%).
1H NMR(300MHz,CDCl3,ppm):δ8.52(d,1H,J=4.2Hz),8.33(d,1H,J=4.5Hz),7.93 (d,1H,J=8.1Hz),7.49(d,1H,J=7.5Hz),7.18-7.12(m,2H),5.08(brs,2H),3.89(s,2H), 3.82(s,2H),2.70(t,2H,J=6.6Hz),2.62(t,2H,J=6.6Hz),2.38(s,3H),1.68-1.58(m,2H), 1.55-1.48(m,2H);EI-MS:324(M)+;HRMS(EI):Calculated value：C18H24N6(M)+:324.2062;Measured value： 324.2059.
Embodiment 42
Compound 44：N1- ((7- (4- methylpiperazine-1-yls) -3H- imidazoles [4,5-b] pyridine -2- bases) methyl)-N1- (pyrrole Pyridine -2- ylmethyls) butane -1,4- diamines
Reaction process is identical with embodiment 38, and 3- methyl -2- pyridine carboxaldehydes are replaced with 2- pyridine carboxaldehydes only in step 7, It is faint yellow jelly (yield 38%) to obtain title compound.
1H NMR(300MHz,CDCl3,ppm):δ8.56(d,1H,J=4.2Hz),7.96(d,1H,J=6.0Hz),7.54 (t,1H,J=7.5Hz),7.33(d,1H,J=7.8Hz),7.11(t,1H,J=6.0Hz),6.35(d,1H,J=5.7Hz),5.58 (brs,2H),3.89(s,2H),3.88(s,4H),3.78(s,2H),2.61-2.53(m,8H),2.32(s,3H),1.57- 1.50(m,2H),1.45-1.41(m,2H);13C NMR(100MHz,CD3OD,ppm):δ160.0,151.6,150.8,149.8, 149.1,145.3,138.7,125.3,125.2,123.9,103.6,61.2,55.7,55.3,48.7,46.2,41.5,29.2, 25.0;EI-MS:408(M)+;HRMS(EI):Calculated value：C22H32N8:408.2750;Measured value：408.2756.
Embodiment 43
Compound 45：2- (((4- aminobutyls) ((7- (4- methylpiperazine-1-yls) -3H- imidazoles [4,5-b] pyridine -2- Base) methyl) amino) methyl) nicotinic acid nitrile
Reaction process is identical with embodiment 38, and 3- methyl -2- pyrroles are replaced with 3- cyano group -2- pyridine carboxaldehydes only in step 7 Pyridine formaldehyde, it is colorless gum (yield 42%) to obtain title compound.
1H NMR(300MHz,CDCl3,ppm):δ8.79(d,1H,J=4.2Hz),7.90-7.86(m,2H),7.26-7.23 (m,1H),6.32(d,1H,J=6.0Hz),4.08(s,2H),3.99(s,2H),3.89(brs,4H),2.82-2.80(m,2H), 2.66-2.64(m,2H),2.59(m,4H),2.34(s,3H),1.62(brs.4H);EI-MS:433(M)+
The preparation flow of wherein 3- cyano group -2- pyridine carboxaldehydes is as follows
Step 1：3- cyano group -2- picolines
By 3- bromine-2-methylpyridines (344mg, 2mmol), Zn (CN) 2 (235mg, 2mmol) and Pd (PPh3)4(75mg, 0.06mmol) it is dissolved in DMF (5mL) mixtures and vacuumizes and changes N2Three times, reaction solution is in N2(175 DEG C) reactions in microwave under protection 2h.After cooling, diluted with EtOAc (60mL), anhydrous sodium sulfate is dried after being washed with saturated common salt, filtering and concentrating, residue column It is white solid (212mg, yield 90%) that chromatography, which obtains title compound,.
1H NMR(300MHz,CDCl3,ppm):δ8.54-8.53(m,1H),7.80(d,1H,J=7.5Hz),7.14-7.16 (m,1H),2.62(s,3H).
Step 2：3- cyano group -2- pyridine carboxaldehydes
By SeO2(129mg, 1.17mmol) and 3- cyano group -2- picolines (125mg, 1.06mmol) are dissolved in DME (2mL), mixture are refluxed 1.5h, cold filtration, and filtrate concentration column chromatography obtains title compound (40mg, yield 30%) For white solid.
1H NMR(300MHz,CDCl3,ppm):δ10.1(s,1H),8.99(d,1H,J=4.5Hz),8.18(d,1H,J= 8.4Hz),7.71-7.66(m,1H).
Embodiment 44
Compound 46：N1- ((1H- benzimidazolyl-2 radicals-yl) methyl)-N1- (5,6,7,8- tetrahydroquinoline -8- bases) butane -1, 4- diamines
Step a：2- (4- hydroxybutyls) isoindoline -1,3- diketone
2- (4- brombutyls) iso-indoles -1,3- diketone (564mg, 2mmol) is dissolved in H2O (1.5mL) and hexamethyl phosphinylidyne Triamine (8.5mL), mixture are reacted 6h at 100 DEG C, let cool, diluted with water, with ether extraction three times.Merge organic phase, have Machine phase anhydrous sodium sulfate is dried, filtering and concentrating.Residue (colorless oil, 353mg, yield 81%) is directly used in anti-in next step Should.
1H NMR(300MHz,CDCl3,ppm):δ7.69-7.65(m,2H),7.58-7.55(m,2H),3.67(brs, 1H),3.59-3.48(m,4H),1.70-1.57(m,2H),1.50-1.41(m,2H).
Step b：4- (1,3- dioxo isoindoline -2- bases) butyraldehyde
Under nitrogen atmosphere, to the anhydrous of 2- (4- hydroxybutyls) isoindoline -1,3- diketone (353mg, 1.61mmol) Dess-Martin oxidants (1.026g, 2.42mmol) are added in dichloromethane (10mL) solution, mixture is stirred at room temperature 2h.Diluted with dichloromethane, washed successively with saturated sodium bicarbonate solution and saturated common salt, the drying of organic phase anhydrous sodium sulfate, Filtering and concentrating, it is white oil thing (190mg, yield 56%) that residue column chromatography, which obtains title compound,.
1H NMR(300MHz,CDCl3,ppm):δ9.75(s,1H),7.82-7.81(m,2H),7.72-7.69(m,2H), 3.72(t,2H,J=6.6Hz),2.52(t,2H,J=7.2Hz),2.04-1.95(m,2H).
Step c：5,6,7,8- tetrahydroquinoline -8- amine
Under stirring, add into the 5mL saturation methanolic ammonia solutions of 6,7- dihydroquinoline -8 (5H) -one (205mg, 1.4mmol) Enter palladium carbon (21mg), 12h is stirred at room temperature in mixture under a hydrogen atmosphere.Filtering removes palladium carbon, filtrate concentration, and residue column chromatography obtains It is red oil (189mg, yield 92%) to title compound.
1H NMR(300MHz,CDCl3,ppm):δ8.32(s,1H),7.28(d,1H,J=6.9Hz),7.00-6.96(m, 1H),3.95-3.93(m,1H),2.71-2.69(m,2H),2.23(brs,2H),2.17-1.61(m,4H).
Step d：5,6,7,8- tetrahydroquinoline -8- amine
Under stirring, to 5,6,7,8- tetrahydroquinoline -8- amine (189mg, 1.275mmol) and 4- (the different dihydros of 1,3- dioxo Indoles -2- bases) butyraldehyde (260mg, 1.20mmol) 1,2- dichloroethane solutions in add sodium triacetoxy borohydride (717mg, 3.384mmol, 2.82eq).2h is stirred at room temperature in mixture, adds saturated sodium bicarbonate solution and is quenched, with dichloro Methane extracts three times, merges organic phase, the drying of organic phase anhydrous sodium sulfate, filtering and concentrating, residue column chromatography obtains titled Compound is pale red grease (263mg, yield 63%).
1H NMR(300MHz,CDCl3,ppm):δ8.34-8.32(m,1H),7.80-7.75(m,2H),7.69-7.64(m, 2H),7.34-7.31(m,1H),7.04-7.00(m,1H),3.77(t,1H,J=6.4Hz),3.68(t,2H,J=6.9Hz), 3.30(brs,1H),2.79-2.70(m,4H),2.18-2.10(m,1H),1.99-1.93(m,1H),1.81-1.56(m,6H).
Step e：2- (chloromethyl) -1H- benzimidazoles
Monoxone (7.5g, 0.08mol) and o-phenylenediamine (7.57g, 0.07mol) are dissolved in 5NHCl (60mL), mixture It is refluxed reaction 7.5h.Let cool, add ammonium hydroxide and neutralize, extracted with ethyl acetate, anhydrous sodium sulfate drying, filtering and concentrating remnants Thing is directly used in for yellow solid (9.5g, yield 81%) to react in next step.
1H NMR(300MHz,CDCl3,ppm):δ7.62-7.59(m,2H),7.30-7.27(m,2H),4.89(s,2H).
Step f：2- (chloromethyl) -1H- benzimidazole -1- carboxylic acid tert-butyl esters
At 0 DEG C, to 2- (chloromethyl)-benzimidazole (224mg, 1.34mmol), di-tert-butyl dicarbonate (587mg, 2.68mmol) and in dichloromethane (6mL) solution of triethylamine (372 μ L, 2.68mmol) add the 4- dimethylaminos of catalytic amount Pyrrole.2h is stirred at room temperature in mixture, is diluted with ethyl acetate, and organic phase is washed with saturated sodium bicarbonate saturated common salt successively, Anhydrous sodium sulfate is dried, filtering and concentrating, and residue (pale yellow oil, 239mg, yield 67%) is directly used in react in next step.
Step g：2- (((4- (1,3- dioxo isoindoline -2- bases) butyl) (5,6,7,8- tetrahydroquinoline -8- bases) Amino) methyl) -1H- benzimidazole -1- carboxylic acid tert-butyl esters
Under stirring, to the second of 2- (chloromethyl) -1H- benzimidazole -1- carboxylic acid tert-butyl esters (263mg, 0.753mmol, 1eq) In nitrile (7.5mL) solution, diisopropylethylamine (187 μ L, 1.13mmol, 1.5eq), 5,6,7,8- tetrahydroquinoline -8- amine are added (239mg, 0.896mmol, 1.2eq) and potassium iodide (13mg, 0.0753mmol).Mixture is under nitrogen atmosphere in 60 DEG C of reactions 15h, lets cool, and concentration, residue is with chloroform and moisture liquid.Organic phase anhydrous sodium sulfate is dried, filtering and concentrating, residue column chromatography It is brown oil (330mg, yield 57%) to obtain title compound.
1H NMR(300MHz,CDCl3,ppm):δ8.38(d,1H,J=4.5Hz),7.78-7.70(m,3H),7.67-7.62 (m,3H),7.32-7.21(m,3H),7.04-6.99(m,1H),4.57(q,J=16.2Hz),4.30-4.26(m,1H),3.51 (t,2H,J=6.9Hz),2.86-2.61(m,4H),2.19-2.15(m,1H),2.01-1.87(m,3H),1.66(s,9H), 1.57-1.37(m,4H).
Step h：2- (4- (((1H- benzimidazolyl-2 radicals-yl) methyl) (5,6,7,8- tetrahydroquinoline -8- bases) amino) butyl) Isoindoline -1,3- diketone
0 DEG C stirring under, to 2- (((4- (1,3- dioxo isoindoline -2- bases) butyl) (5,6,7,8- tetrahydroquinolines - 8- yls) amino) methyl) and -1H- benzimidazole -1- carboxylic acid tert-butyl esters (330mg, 0.569mmol) ethyl acetate (2mL) solution Middle addition 6NHCl (1mL).4h is stirred at room temperature in mixture, is neutralized with saturated sodium carbonate solution, liquid separation, the anhydrous sulphur of organic phase Sour sodium drying, filtering and concentrating, residue (white foam solid, 62mg, yield 96%) is directly used in react in next step.
Step i：N1- ((1H- benzimidazolyl-2 radicals-yl) methyl)-N1- (5,6,7,8- tetrahydroquinoline -8- bases) butane -1,4- Diamines
Under stirring, to 2- (4- (((1H- benzimidazolyl-2 radicals-yl) methyl) (5,6,7,8- tetrahydroquinoline -8- bases) amino) fourths Base) isoindoline -1,3- diketone (262mg, 0.546mmol) 5mL ethanol solutions in add hydrazine hydrate (250 μ L, 4.370mmol), mixture is refluxed reaction 2h, lets cool, and filters, and filtrate concentration, residue column chromatography obtains title compound (97mg, yield 62%) is colorless gum.
1H NMR(300MHz,CDCl3,ppm):δ8.56(d,1H,J=4.2Hz),7.58-7.55(m,2H),7.37(d, 1H,J=7.2Hz),7.18-7.07(m,3H),4.08-3.93(m,3H),2.86-2.49(m,6H),2.20-1.62(m,4H), 1.48-1.41(m,4H);13C NMR(100MHz,CDCl3,ppm):δ156.1,153.6,146.4,137.9,137.7, 134.8,122.2,122.1,114.9,61.4,50.7,48.8,39.3,29.0,28.9,26.0,21.5,21.2;EI-MS: 349(M)+;HRMS(EI):Calculated value：C21H27N5(M)+:349.2266;Measured value：349.2274.
Embodiment 45
Compound 47：3- (2- (((4- aminobutyls) ((7- (4- methylpiperazine-1-yls) -3H- imidazoles [4,5-b] pyridine - 2- yls) methyl) amino) methyl) pyridin-3-yl) propionitrile
Reaction process is identical with embodiment 38, (is synthesized with 3- (2- formylpyridine -3- bases) propionitrile only in step 7 Journey is shown in embodiment 1) 3- methyl -2- pyridine carboxaldehydes are replaced, it is colorless gum (yield 28%) to obtain title compound.
1H NMR(300MHz,CD3OD,ppm):δ8.47(d,1H,J=4.5Hz),8.04(d,1H,J=6.0Hz),7.75 (d,1H,J=7.8Hz),7.37-7.34(m,1H),6.69(d,1H,J=6.0Hz),4.16(brs,4H),4.02(s,2H), 3.94(s,2H),3.38(brs,4H),3.09-3.05(m,2H),2.89-2.79(m,7H),2.67-2.65(m,2H),1.64- 1.61(m,4H);13C NMR(100MHz,CD3OD,ppm):δ157.7,151.7,151.0,148.6,148.5,145.2, 140.4,136.4,125.2,125.1,121.1,104.4,59.4,55.6,55.0(2C),53.2,47.3,47.2,44,6, 41.0,28.6,27.0,25.2,19.0;EI-MS:461(M)+;HRMS(EI):Calculated value：C25H35N9:461.3015;Actual measurement Value：461.3022.
Embodiment 46
Compound 48：3- (2- ((methyl ((7- (4- methylpiperazine-1-yls) -3H- imidazoles [4,5-b] pyridine -2- bases) first Base) amino) methyl) pyridin-3-yl) propionitrile
Reaction process is identical with embodiment 37, (is synthesized with 3- (2- formylpyridine -3- bases) propionitrile only in step 6 Journey is shown in embodiment 1) 3- methyl -2- pyridine carboxaldehydes are replaced, it is colorless gum (yield 33%) to obtain title compound.
1H NMR(300MHz,CDCl3,ppm):δ8.53(1H,dd,J1=4.8Hz,J2=1.2Hz),7.99(d,1H,J= 6.0Hz),7.59(1H,dd,J1=7.8Hz,J2=1.2Hz),7.27-7.23(m,1H),6.40(d,1H,J=5.7Hz),3.97 (t,4H,J=4.8Hz),3.80(s,2H),3.79(s,2H),3.02(t,2H,J=7.2Hz),2.74(t,2H,J=7.2Hz), 2.66(t,4H,J=4.8Hz),2.39(s,6H);13C NMR(100MHz,CDCl3,ppm):δ156.0,149.5,147.7, 147.6,147.3,143.9,138.0,133.8,124.8,123.2,119.0,101.8,60.2,54.7,53.9,47.5, 46.0,43.1,27.7,18.4;EI-MS:404(M+);HRMS(EI):Calculated value：C22H28N8(M)+:404.2437;Measured value： 404.2437.
Embodiment 47
Compound 49：1- (7- (4- methylpiperazine-1-yls) -3H- imidazoles [4,5-b] pyridine -2- bases) ((3- first of-N, N- bis- Yl pyridines -2- bases) methyl) methylamine
Step 1 arrives step 5 to step 5 with step 1 in embodiment 37.
Step 6：1- (7- (4- methylpiperazine-1-yls) -3H- imidazoles [4,5-b] pyridine -2- bases) ((3- methyl of-N, N- bis- Pyridine -2- bases) methyl) methylamine
By (7- (4- methylpiperazine-1-yls) -1H- imidazoles [4,5-b] pyridine -2- bases) methylamine (48mg, 0.19mmol, 1eq) and 3- methyl -2- pyridine carboxaldehydes (47mg, 0.39mmol, 2eq) are dissolved in 2mL CH3OH, adds NaCNBH3(10mg, 0.16mmol, 0.8eq), mixture is stirred at room temperature 2h. and is spin-dried for reaction solution, residue column chromatography (DCM:NH3·CH3OH=15: 1) it is faint yellow jelly to obtain title compound (17mg, yield 20%).
1H NMR(300MHz,CDCl3,ppm):δ2.20(s,6H),2.39(s,3H),2.67(t,4H,J=4.8Hz), 3.87(s,4H),3.94(t,4H,J=4.5Hz),3.98(s,2H),6.42(d,1H,J=5.7Hz),7.06-7.10(m,2H), 7.37(d,2H,J=7.5Hz),8.06(d,1H,J=6.0Hz),8.45(d,2H,J=3.6Hz);EI-MS:456(M+);HRMS (EI):Calculated value：C26H32N8(M)+:456.2750;Measured value：456.2759.
Embodiment 48
Compound 50：N- methyl isophthalic acids-(7- (4- methylpiperazine-1-yls) -3H- imidazoles [4,5-b] pyridine -2- bases)-N- ((3- phenylpyridine -2- bases) methyl) methylamine
Reaction process is identical with embodiment 37, and 3- methyl -2- pyrroles are replaced with 3- phenyl -2- pyridine carboxaldehydes only in step 6 Pyridine formaldehyde, it is white gum thing (yield 58%) to obtain title compound.
1H NMR(300MHz,CDCl3,ppm):δ8.72(d,1H,J=5.1Hz),8.02(d,1H,J=5.7Hz),7.64 (d,1H,J=7.8Hz),7.44-7.42(m,5H),7.34-7.30(m,1H),6.39(d,1H,J=6.0Hz),3.88-3.86 (m,6H),3.71(s,2H),2.60(t,4H,J=4.8Hz),2.35(s,3H),2.25(s,3H);EI-MS:427(M)+;HRMS (EI):Calculated value：C25H29N7:427.2484;Measured value：427.2478.
The preparation flow of wherein 3- phenyl -2- pyridine carboxaldehydes is as follows：
Step 1：2- methyl -3- phenylpyridines
3- bromine-2-methylpyridines (126mg, 0.733mmol) are dissolved in toluene (1mL), stir lower addition phenyl boric acid Ethanol (1.5mL) solution of (268mg, 2.198mmol), adds the sodium carbonate liquor (2.93mL) of 2M, adds Pd [P (Ph)3]4(110mg, 0.088mmol).Mixture, which vacuumizes, changes N2After three times, in N2Flow back 24h under atmosphere.After letting cool, liquid separation, Organic layer is isolated, water layer is extracted twice with ether again, merges organic layer, after anhydrous sodium sulfate drying, filtering and concentrating, residue Column chromatography obtains yellow oil (105mg, yield 86%).
1H NMR(300MHz,CDCl3,ppm):δ8.48(d,1H,J=5.1Hz),7.49(d,1H,J=7.8Hz),7.44- 7.35(m,3H),7.29(d,2H,J=6.9Hz),7.17-7.13(m,1H),2.50(s,3H).
Step 2：3- phenyl -2- pyridine carboxaldehydes
2- methyl -3- phenylpyridines (392mg, 2.32mmol) are dissolved in 10mL dioxane, add selenium dioxide (772mg, 6.96mmol), mixture are refluxed overnight, let cool filtering, filtrate concentration residue column chromatography obtains Red oil Thing (260mg, yield 61%).
1H NMR(300MHz,CDCl3,ppm):δ10.10(s,1H),8.81(d,1H,J=5.1Hz),7.92(d,1H,J= 7.8Hz),7.44-7.35(m,3H),7.29(d,2H,J=6.9Hz),7.17-7.13(m,1H).
Embodiment 49
Compound 51：N1- ((7- (4- methylpiperazine-1-yls) -3H- imidazoles [4,5-b] pyridine -2- bases) methyl)-N1- ((3- phenylpyridine -2- bases) methyl) butane -1,4- diamines
Reaction process is identical with embodiment 38, and with 3- phenyl -2- pyridine carboxaldehydes, (building-up process is shown in implementation only in step 7 Example 48) 3- methyl -2- pyridine carboxaldehydes are replaced, it is white gum thing (yield 78%) to obtain title compound.
1H NMR(300MHz,CDCl3,ppm):δ8.76(dd,1H,J1=4.8Hz,J2=1.2Hz),8.03(d,1H,J= 5.7Hz),7.62(dd,1H,J1=7.8Hz,J2=1.2Hz),7.45-7.30(m,6H),6.40(d,1H,J=6.0Hz),3.89- 3.86(m,6H),3.77(s,2H),2.60(t,4H,J=4.8Hz),2.53(s,2H),2.42(t,2H,J=6.6Hz),2.35 (s,3H),1.37-1.29(m,4H)；EI-MS:484(M)+;HRMS(EI):Calculated value：C28H36N8:484.3063;Measured value： 484.3068.
Embodiment 50
Compound 52：N1- ((3- (2,6- 3,5-dimethylphenyls) pyridine -2- bases) methyl)-N1- ((7- (4- methyl piperazines -1- Base) -3H- imidazoles [4,5-b] pyridine -2- bases) methyl) butane -1,4- diamines
Reaction process is identical with embodiment 38, is replaced only in step 7 with 3- (2,6- 3,5-dimethylphenyl) -2- pyridine carboxaldehydes 3- methyl -2- pyridine carboxaldehydes, it is colorless gum (yield 71%) to obtain title compound.
1H NMR(300MHz,CDCl3,ppm):δ8.75(d,1H,J=4.8Hz),8.00(d,1H,J=5.7Hz),7.43 (d,1H,J=7.5Hz),7.34-7.30(m,1H),7.21-7.16(m,1H),7.10(d,2H,J=7.2Hz),6.38(d,1H,J =5.7Hz),4.90(brs,2H),3.86(s,4H),3.81(s,2H),3.47(s,2H),2.59-2.51(m,6H),2.38(t, 2H,J=6.0Hz),2.32(s,3H),1.92(s,6H),1.26-1.24(m,4H);EI-MS:512(M)+;HRMS(EI):Calculate Value：C30H40N8:512.3376;Measured value：512.3384.
The preparation flow of wherein 3- (2,6- 3,5-dimethylphenyls) -2- pyridine carboxaldehydes is as follows:
Step 1：3- bromo-2-pyridyl formaldehyde
3- bromine-2-methylpyridines (258mg, 1.5mmol) are dissolved in dioxane (5mL), stir lower addition selenium dioxide (666mg, 6.0mmol), mixture reflux 48h let cool filtering, filtrate concentration, and residue thing column chromatography obtains faint yellow solid (175mg, yield 63%).
1H NMR(300MHz,CDCl3,ppm):δ10.22(s,1H),8.74(dd,1H,J1=4.8Hz,J2=1.2Hz), 8.03(dd,1H,J1=7.8Hz,J2=1.2Hz),7.38-7.34(m,1H).
Step 2：3- (2,6- 3,5-dimethylphenyls) -2- pyridine carboxaldehydes
3- bromo-2-pyridyls formaldehyde (125mg, 0.672mmol) is dissolved in toluene (2mL), stirs lower addition 2,6- dimethyl Ethanol (1mL) solution of phenyl boric acid (120mg, 0.806mmol), adds the sodium carbonate liquor (3mL) of 2M, adds Pd [P (Ph)3]4(100mg, 0.0806mmol).Mixture, which vacuumizes, changes N2After three times, in N2Flow back 24h under atmosphere.After letting cool, point Liquid, isolates organic layer, and water layer is extracted twice with ether again, merges organic layer, after anhydrous sodium sulfate drying, filtering and concentrating is residual It is white solid (51mg, yield 36%) that excess column chromatography, which obtains title compound,.
1H NMR(300MHz,CDCl3,ppm):δ9.92(s,1H),8.86(dd,1H,J1=3.9Hz,J2=2.1Hz), 7.60-7.58(m,2H),7.27-7.22(m,1H),7.14(d,2H,J=7.8Hz),1.93(s,6H).
Embodiment 51
Compound 53：N1- ((3- bromopyridine -2- bases) methyl)-N1- ((7- (4- methylpiperazine-1-yls) -3H- imidazoles [4, 5-b] pyridine -2- bases) methyl) butane -1,4- diamines
Reaction process is identical with embodiment 38, and with 3- bromo-2-pyridyls formaldehyde, (building-up process is shown in embodiment only in step 7 50) 3- methyl -2- pyridine carboxaldehydes are replaced, it is faint yellow jelly (yield 54%) to obtain title compound.
1H NMR(300MHz,CDCl3,ppm):δ8.61(dd,1H,J1=4.8Hz,J2=1.8Hz),7.95(d,1H,J= 6.0Hz),7.82(dd,1H,J1=7.8Hz,J2=1.8Hz),7.06(dd,1H,J1=8.1Hz,J2=4.8Hz),6.36(d,1H, J=6.0Hz),4.68(brs,2H),3.99(s,2H),3.95(s,2H),3.87(t,4H,J=4.8Hz),2.65(t,4H,J= 6.6Hz),2.59(t,4H,J=4.8Hz),2.34(s,3H),1.62-1.41(m,4H);13C NMR(100MHz,CDCl3,ppm) δ156.6,149.8,149.4,147.6,147.5,143.4,140.7,125.0,123.6,121.4,101.6,58.5,55.1, 54.8,52.7,47.7,46.2,41.0,29.9,24.7;EI-MS:486(M)+;HRMS(EI):Calculated value：C22H31BrN8: 486.1855;Measured value：486.1854.
Embodiment 52
Compound 54：N1- (2- aminomethyl phenyls)-N1- ((7- (4- methylpiperazine-1-yls) -3H- imidazoles [4,5-b] pyridine - 2- yls) methyl) butane -1,4- diamines
Reaction process is identical with embodiment 38, and 3- methyl -2- pyridine first is replaced with 2- tolyl aldehydes only in step 7 Aldehyde, it is colorless gum (yield 80%) to obtain title compound.
1H NMR(300MHz,CDCl3,ppm):δ7.91(brs,0.5H,imidazole NH),7.80(d,1H,J= 5.7Hz),7.39(brs,0.5H,imidazole NH),7.32(d,1H,J=7.2Hz),7.07-6.95(m,3H),6.29(d, 1H,J=5.7Hz),5.41(brs,2H),3.90(s,4H),3.78(s,2H),3.60(s,2H),2.71(s,2H),2.59(s, 4H),2.46(s,2H),2.34(s,3H),2.24(s,3H),1.56(s,4H);EI-MS:421(M)+;HRMS(EI):Calculate Value：C24H35N7:421.2954;Measured value：421.2954.
Embodiment 53
Compound 55：N1- ((1H- imidazoles -2- bases) methyl)-N1- ((7- (4- methylpiperazine-1-yls) -3H- imidazoles [4,5- B] pyridine -2- bases) methyl) butane -1,4- diamines
Reaction process is identical with embodiment 38, and 3- methyl -2- pyridine carboxaldehydes are replaced with 2- imidazole formaldehydes only in step 7, It is colorless gum (yield 59%) to obtain title compound.
1H NMR(300MHz,CDCl3,ppm):δ7.94(d,1H,J=5.7Hz),6.93(s,2H),6.38(d,1H,J= 6.0Hz),3.89(t,4H,J=4.5Hz),3.79(s,2H),3.69(s,2H),2.65-2.58(m,6H),2.48(t,2H,J= 6.0Hz),2.35(s,3H),1.63-1.52(m,4H),EI-MS:397(M)+;HRMS(EI):Calculated value：C20H31N9: 397.2702;Measured value：397.2712.
Embodiment 54
Compound 56：N1- ((1- methyl isophthalic acid H- imidazoles -2- bases) methyl)-N1- ((7- (4- methylpiperazine-1-yls) -3H- miaows Azoles 4,5-b] pyridine -2- bases) methyl) butane -1,4- diamines
Reaction process is identical with embodiment 38, only in step 7 with 1- methyl isophthalic acid H- imidazoles -2- formaldehyde replace 3- methyl - 2- pyridine carboxaldehydes, it is colorless gum (yield 30%) to obtain title compound.
1H NMR(300MHz,CDCl3,ppm):δ7.97(d,1H,J=5.7Hz),6.95(s,1H),6.81(s,1H), 6.38(d,1H,J=5.7Hz),3.89(s,4H),3.74(s,2H),3.69(s,2H),3.60(s,3H),2.71(t,2H,J= 6.6Hz),2.61-2.52(m,6H),2.34(s,3H),1.67-1.58(m,2H),1.54-1.44(m,2H);EI-MS:411 (M)+;HRMS(EI):Calculated value：C21H33N9:411.2859;Measured value：411.2852.
The preparation flow of wherein 1- methyl isophthalic acids H- imidazoles -2- formaldehyde is as follows：
It is stirred at room temperature down, to 1H- imidazoles -2- formaldehyde (250mg, 2.6mmol) and K2CO3The DMF of (431mg, 3.12mmol) Iodomethane (442mg, 3.12mmol) is added in (2.5mL) solution.Mixture stirs 5h under the conditions of 50 DEG C, lets cool and filters out admittedly Body.Water is added into filtrate, then is extracted with ethyl acetate three times, anhydrous sodium sulfate is done after combining extraction liquid is washed with saturated common salt It is dry.It is pale yellow oil (168mg, yield 59%) that filtering and concentrating, which is drained to obtain 1- methyl isophthalic acid H- imidazoles -2- formaldehyde,.
1H NMR(300MHz,CDCl3,ppm):δ9.74(s,1H),7.20(s,1H),7.06(s,1H),3.95(s,3H).
Embodiment 55
Compound 57：N1- (the chloro- 6- nitrobenzyls of 2-)-N1- ((7- (4- methylpiperazine-1-yls) -3H- imidazoles [4,5-b] Pyridine -2- bases) methyl) butane -1,4- diamines
Reaction process is identical with embodiment 38, and 3- methyl -2- pyrroles are replaced with the chloro- 6- nitrobenzaldehydes of 2- only in step 7 Pyridine formaldehyde, it is colorless gum (yield 80%) to obtain title compound.
1H NMR(300MHz,CDCl3,ppm):δ7.99(d,1H,J=5.7Hz),7.50-7.47(m,2H),7.26(t, 1H,J=7.8Hz),6.37(d,1H,J=6.0Hz),4.18(s,2H),3.89(s,4H),3.77(s,2H),2.63-2.57(m, 6H),2.44(t,2H,J=7.2Hz),2.35(s,3H),1.54-1.44(m,2H),1.36-1.24(m,2H);EI-MS:486 (M)+;HRMS(EI):Calculated value：C23H31ClN8O2:486.2258;Measured value：486.2265.
Embodiment 56
Compound 58：N1- (furans -2- ylmethyls)-N1- ((7- (4- methylpiperazine-1-yls) -3H- imidazoles [4,5-b] pyrrole Pyridine -2- bases) methyl) butane -1,4- diamines
Reaction process is identical with embodiment 38, and 3- methyl -2- pyridine carboxaldehydes are replaced with 2 furan carboxyaldehyde only in step 7, It is white gum thing (yield 56%) to obtain title compound.
1H NMR(300MHz,CDCl3,ppm):δ8.02(d,1H,J=6.0Hz),7.36(s,1H),6.40(d,1H,J= 6.0Hz),6.30-6.28(m,1H),6.22(d,1H,J=3.0Hz),3.94-3.90(m,6H),3.76(s,2H),2.66- 2.59(m,6H),2.52(t,2H,J=7.2Hz),2.35(s,3H),1.62-1.53(m,2H),1.48-1.38(m,2H);EI- MS:397(M)+;HRMS(EI):Calculated value：C21H31N7O:397.2590;Measured value：397.2587.
Embodiment 57
Compound 59：N1- ((7- (4- methylpiperazine-1-yls) -3H- imidazoles [4,5-b] pyridine -2- bases) methyl)-N1- ((3- morpholine pyridine -2- bases) methyl) butane -1,4- diamines
Reaction process is identical with embodiment 38, and 3- methyl -2- is replaced with morpholinyl -2- pyridine carboxaldehydes only in step 7 Pyridine carboxaldehyde, it is colorless gum (yield 26%) to obtain title compound.
1H NMR(300MHz,CDCl3,ppm):δ8.48(d,1H,J=4.5Hz),8.02(d,1H,J=5.7Hz),7.40 (d,1H,J=7.8Hz),7.26-7.22(m,1H),6.40(d,1H,J=5.7Hz),4.41(brs,2H),3.95(s,2H), 3.89-3.84(m,10H),3.02(t,4H,J=4.2Hz),2.65-2.56(m,8H),2.35(s,3H),1.62-1.52(m, 2H),1.44-1.34(m,2H);EI-MS:493(M)+;HRMS(EI):Calculated value：C26H39N9O:493.3278;Measured value： 486.3286.
The preparation flow of wherein 3- morpholine -2s-pyridine carboxaldehyde is as follows：
Step 1：3- morpholine -2s-picoline
By 3- bromine-2-methylpyridines (1.2mmol, 206mg), morpholine (1.44mmol, 125mg), Pd2(dba)3 (0.024mmol, 22mg), (±) BINAP (0.048mmol, 30mg), NaOtBu (1.68mmol, 161mg), and toluene (4mL) After adding dry reaction bulb, then use N2Replace 5min.Reaction solution is in N2Disappear under atmosphere in 70 ° of reactions to raw material.Let cool to room Temperature, adds ether (10mL), is dried with anhydrous sodium sulfate after saturated common salt washing three times, filtering and concentrating, residue column chromatography obtains To title compound as yellow grease (yield 90%).
1H NMR(300MHz,CDCl3,ppm):δ8.16(d,1H,J=4.8Hz),7.22(d,1H,J=8.1Hz),7.06- 7.02(m,1H),3.80(t,4H,J=4.5Hz),2.84(t,4H,J=4.5Hz),2.48(s,3H).
Step 2：3- morpholine -2s-pyridine carboxaldehyde
The mixture of selenium dioxide (528mg, 4.76mmol) and dioxane (8mL) is heated to 80 DEG C.Add 4- (2- Picoline -3- bases) morpholine (212mg, 1.19mmol) dioxane solution (2mL).Mixture reacts under the conditions of 80 DEG C 18h, lets cool filtering, and filtrate concentrates, and it is yellow oil (yield 20%) to obtain title compound after residue column chromatography.
1H NMR(300MHz,CDCl3,ppm):δ10.16(s,1H),8.42(t,1H,J=3.0Hz),7.42(d,1H,J= 3.0Hz),3.95-3.92(m,4H),3.15-3.12(m,4H).
Embodiment 58
Compound 60：N1- ((3- (4- methoxyphenyls) pyridine -2- bases) methyl)-N1- ((7- (4- methyl piperazines -1- Base) -3H- imidazoles [4,5-b] pyridine -2- bases) methyl) butane -1,4- diamines
Reaction process is identical with embodiment 38, and 3- is replaced with 3- (4- methoxyphenyls) pyridine-2-formaldehyde only in step 7 Methyl -2- pyridine carboxaldehydes, it is faint yellow jelly (yield 61%) to obtain title compound.
1H NMR(300MHz,CDCl3,ppm):δ8.71(d,1H,J=4.5Hz),8.02(d,1H,J=6.0Hz),7.61 (d,1H,J=7.8Hz),7.35-7.26(m,3H),6.96(d,2H,J=8.1Hz),6.40(d,1H,J=5.7Hz),4.80 (brs,2H),3.91(s,6H),3.86(s,3H),3.76(s,2H),2.60-2.56(m,6H),2.45(t,2H,J=6.6Hz), 2.35(s,3H),1.41-1.38(m,4H);.EI-MS:514(M)+;HRMS(EI):Calculated value：C29H38N8O:514.3169;It is real Measured value：514.3171.
The preparation of 3- (4- methoxyphenyls) -2- pyridine carboxaldehydes and the preparation of 3- phenyl -2- pyridine carboxaldehydes in embodiment 48 It is similar, phenyl boric acid is only changed into 4- methoxyphenylboronic acids.
3- (4- methoxyphenyls) -2- picolines
1H NMR(300MHz,CDCl3,ppm):δ8.46(d,1H,J=4.5Hz),7.49(d,1H,J=7.8Hz),7.24 (d,2H,J=8.7Hz),7.18-7.14(m,1H),6.97(d,2H,J=8.1Hz),3.85(s,3H),2.51(s,3H).
3- (4- methoxyphenyls) -2- pyridine carboxaldehydes
1H NMR(300MHz,CDCl3,ppm):δ10.09(s,1H),8.79(d,1H,J=4.5Hz),7.79(d,1H,J= 7.8Hz),7.54-7.49(m,1H),7.30(d,2H,J=8.4Hz),7.01(d,2H,J=8.4Hz),3.86(s,3H).
Embodiment 59
Compound 61：N1- ((3-Methoxy Pyridine -2- bases) methyl)-N1- ((7- (4- methylpiperazine-1-yls) -3H- imidazoles [4,5-b] pyridine -2- bases) methyl) butane -1,4- diamines
Reaction process is identical with embodiment 38, and 3- methyl -2- is replaced with 3- methoxyl group -2- pyridine carboxaldehydes only in step 7 Pyridine carboxaldehyde, it is colorless gum (yield 33%) to obtain title compound.
1H NMR(300MHz,CDCl3,ppm):δ8.26-8.24(m,1H),7.98(d,1H,J=6.0Hz),7.22-7.20 (m,2H),6.39(d,1H,J=6.0Hz),3.94(s,3H),3.91(s,6H),3.86(s,2H),2.69-2.59(m,8H), 2.36(s,3H),1.62-1.53(m.2H),1.49-1.42(m,2H);13C NMR(100MHz,CDCl3,ppm):δ154.2, 150.5,149.5,147.8,147.5,143.4,140.3,125.2,123.3,117.7,101.6,55.5,54.9,54.7, 54.2,52.6,47.7,46.2,41.3,30.4,24.6;EI-MS:438(M)+;HRMS(EI):Calculated value：C23H34N8O: 438.2856;Measured value：486.2873.
The preparation flow of wherein 3- methoxyl groups -2- pyridine carboxaldehydes is as follows：
Step 1：3- methoxyl group -2- picolines
3- bromine-2-methylpyridines (860mg, 5mmol) are dissolved in DMSO (10mL), add CH3ONa (20mmol, 1.080g), mixture reacts 12h at 100 DEG C, lets cool, and adds water, with ether extraction three times.Merge organic layer, anhydrous sodium sulfate Dry, filtering and concentrating, it is yellow oil (yield 43%) that residue column chromatography, which obtains title compound,.
1H NMR(300MHz,CDCl3,ppm):δ8.30(d,1H,J=5.7Hz),6.66-6.62(m,2H),3.82(s, 3H),2.50(s,3H).
Step 2：3- methoxyl group -2- pyridine carboxaldehydes
The mixture of selenium dioxide (478mg, 4.30mmol) and dioxane (8mL) is heated to 80 DEG C.Add 3- first The dioxane solution (2mL) of epoxide -2- picolines (265mg, 2.15mmol).Mixture reacts 18h under the conditions of 80 DEG C, Filtering is let cool, filtrate concentrates, and it is yellow jelly (yield 27%) to obtain title compound after residue column chromatography.
1H NMR(300MHz,CDCl3,ppm):δ10.34(s,1H),8.40(d,1H,J=3.9Hz),7.51-7.40(m, 2H),3.97(s,3H);ESI-MS:138.0(M+H)+
Embodiment 60
Compound 62：N1- ((7- (4- methylpiperazine-1-yls) -3H- imidazoles [4,5-b] pyridine -2- bases) methyl)-N1- ((3- (4- (trifluoromethyl) phenyl) pyridine -2- bases) methyl) butane -1,4- diamines
Reaction process is identical with embodiment 38, with 3- (4- (trifluoromethyl) phenyl) -2- pyridine carboxaldehyde generations only in step 7 For 3- methyl -2- pyridine carboxaldehydes, it is colorless gum (yield 88%) to obtain title compound.
1H NMR(300MHz,CDCl3,ppm):δ8.75(dd,1H,J1=4.8Hz,J2=1.2Hz),7.98(d,1H,J= 6.0Hz),7.68(d,1H,J=8.4Hz),7.60-7.53(m,3H),7.33-7.31(m,1H),6.37(d,1H,J=5.4Hz), 5.21(brs,2H),3.87(s,6H),3.71(s,2H),2.64-2.56(m,6H),2.45(t,2H,J=6.3Hz),2.33(s, 3H),1.44-1.35(m,4H);EI-MS:552(M)+;HRMS(EI):Calculated value：C29H35F3N8:552.2937;Measured value： 552.2939.
The preparation of 3- (4- trifluoromethyls) -2- pyridine carboxaldehydes and the system of 3- phenyl -2- pyridine carboxaldehydes in embodiment 48 It is standby similar, phenyl boric acid is only changed into 4- trifluoromethylbenzene boronic acids.
3- (4- trifluoromethyls) -2- picolines
1H NMR(300MHz,CDCl3,ppm):δ8.51(dd,1H,J1=4.8Hz,J2=1.8Hz),7.67(d,2H,J= 8.4Hz),7.47(dd,1H,J1=7.8Hz,J2=1.8Hz),7.41(d,2H,J=8.1Hz),7.20-7.16(m,1H),2.46 (s,3H).
3- (4- trifluoromethyls) -2- pyridine carboxaldehydes
1H NMR(300MHz,CDCl3,ppm):δ10.10(s,1H),8.88(dd,1H,J1=4.8Hz,J2=1.2Hz), 7.77-7.72(m,3H),7.59(dd,1H,J1=7.8Hz,J2=4.5Hz),7.47(d,2H,J=7.8Hz).
Embodiment 61
Compound 63：N1- ((7- (4- methylpiperazine-1-yls) -3H- imidazoles [4,5-b] pyridine -2- bases) methyl)-N1- ((3 methyl thiophene -2- bases) methyl) butane -1,4- diamines
Reaction process is identical with embodiment 38, and 3- methyl -2- pyrroles are replaced with 3- methyl -2 thiophene carboxaldehyde only in step 7 Pyridine formaldehyde, it is white gum thing (yield 60%) to obtain title compound.
1H NMR(300MHz,CDCl3,ppm):δ7.85(d,1H,J=5.4Hz),7.06(d,1H,J=5.1Hz),6.73 (d,1H,J=4.8Hz),6.33(d,1H,J=6.0Hz),3.94(s,4H),3.87(s,2H),3.86(s,2H),2.92(s, 2H),2.58(t,4H,J=4.5Hz),2.50(s,2H),2.34(s,3H),2.16(s,3H),1.72(s,4H);EI-MS:427 (M)+;HRMS(EI):Calculated value：C22H33N7S:427.2518;Measured value：427.2517.
Embodiment 62
Compound 64：2- (((4- aminobutyls) ((7- (4- methylpiperazine-1-yls) -3H- imidazoles [4,5-b] pyridine -2- Base) methyl) amino) methyl) benzonitrile
Reaction process is identical with embodiment 38, and 3- methyl -2- pyridine first is replaced with 2- formylbenzonitriles only in step 7 Aldehyde, it is white gum thing (yield 34%) to obtain title compound.
1H NMR(300MHz,CDCl3,ppm):δ7.96(d,1H,J=5.7Hz),7.59-7.55(m,2H),7.39(t, 1H,J=7.8Hz),7.28-7.23(m,1H),6.37(d,1H,J=5.7Hz),5.28(brs,2H),3.92(s,6H),3.89 (s,2H),2.69-2.54(m,8H),2.35(s,3H),1.67-1.58(m,2H),1.50-1.41(m,2H);EI-MS:433 (M)+HRMS(EI):Calculated value：C24H32N8:432.2750;Measured value：432.2752.
Embodiment 63
Compound 65：2- (((4- aminobutyls) ((7- (4- methylpiperazine-1-yls) -3H- imidazoles [4,5-b] pyridine -2- Base) methyl) amino) methyl) -3,5- chlorophenesic acids
Reaction process is identical with embodiment 38, only in step 7 with 2,4- dichloro-6-hydroxies benzaldehyde replace 3- methyl- 2- pyridine carboxaldehydes, it is faint yellow jelly (yield 24%) to obtain title compound.
1H NMR(300MHz,CD3OD,ppm):δ7.93(d,1H,J=5.7Hz),6.82(d,1H,J=2.1Hz),6.69 (d,1H,J=1.8Hz),6.57(d,1H,J=5.7Hz),4.02(s,2H),3.96(s,2H),3.88-3.84(m,6H),2.66- 2.63(m,6H),2.37(s,3H),1.72-1.60(m,4H);EI-MS:491(M)+;HRMS(EI):Calculated value： C23H31Cl2N7O:491.1967;Measured value：491.1945.
Embodiment 64
Compound 66：N1- ((3- (1H- indoles -1- bases) pyridine -2- bases) methyl)-N1- ((7- (4- methyl piperazines -1- Base) -3H- imidazoles [4,5-b] pyridine -2- bases) methyl) butane -1,4- diamines
Reaction process is identical with embodiment 38, and 3- is replaced with 3- (1H- indoles -1- bases) -2- pyridine carboxaldehydes only in step 7 Methyl -2- pyridine carboxaldehydes, it is faint yellow jelly (yield 28%) to obtain title compound.
1H NMR(300MHz,CDCl3,ppm):δ8.62(s,1H),7.90(d,1H,J=5.4Hz),7.76(d,1H,J= 6.0Hz),7.66(d,1H,J=7.5Hz),7.55(d,1H,J=7.2Hz),7.44-7.33(m,2H),7.17-7.07(m,2H), 6.41-6.30(m,2H),3.83(s,6H),3.60-3.46(m,2H),2.56(s,6H),2.46-2.42(m,2H),2.33(s, 3H),1.30-1.18(m,4H);EI-MS:523(M)+;HRMS(EI):Calculated value：C30H37N9:523.3172;Measured value： 523.3120.
The preparation flow of wherein 3- (1H- indoles -1- bases) -2- pyridine carboxaldehydes is as follows：
Step 1：1- (2- picoline -3- bases) -1H- indoles
Indoles (117mg, 1mmol) and 3- bromine-2-methylpyridines (172mg, 1mmol) are dissolved in DMF (3mL), add carbon Sour potassium (138mg, 1mmol) and CuO (7mg, 1mmol), vacuumize and change N2After three times, mixture is in N2The 16h. that flows back under atmosphere is put After cold, with DCM and moisture liquid.After organic layer is washed with saturated common salt, anhydrous sodium sulfate drying, filtering and concentrating, residue column layer It is white solid (yield 53%) that title compound is obtained after analysis
1H NMR(300MHz,CDCl3,ppm):δ8.63(d,1H,J=4.8Hz),7.74-7.71(m,1H),7.64(d, 1H,J=8.1Hz),7.32-7.28(m,1H),7.22-7.16(m,3H),7.04-7.01(m,1H),6.734(d,1H,J= 2.7Hz),2.34(s,3H).
Step 2：3- (1H- indoles -1- bases) -2- pyridine carboxaldehydes
The mixture of selenium dioxide (234mg, 2.113mmol) and dioxane (3mL) is heated to 80 DEG C.Add 1- The dioxane solution (2mL) of (2- picoline -3- bases) -1H- indoles (110mg, 0.528mmol).Mixture is in 80 DEG C of bars 18h is reacted under part, lets cool filtering, filtrate concentrates, and it is red solid (60%) to obtain title compound after residue column chromatography.
1H NMR(300MHz,CDCl3,ppm):δ10.06(s,1H),8.96(d,1H,J=3.9Hz),7.90(d,1H,J= 7.8Hz),7.78-7.74(m,3H),7.52(t,2H,J=7.8Hz),7.20(t,1H,J=7.5Hz),6.51(d,1H,J= 7.8Hz).
Embodiment 65
Compound 67：N1- ((3,5- difluoro pyridine -2- bases) methyl)-N1- ((7- (4- methylpiperazine-1-yls) -3H- imidazoles [4,5-b] pyridine -2- bases) methyl) butane -1,4- diamines
Reaction process is identical with embodiment 38, and 3- methyl -2- is replaced with the fluoro- 2- pyridine carboxaldehydes of 3,5- bis- only in step 7 Pyridine carboxaldehyde, it is faint yellow jelly (yield 59%) to obtain title compound.
1H NMR(300MHz,CDCl3,ppm):δ8.32(d,1H,J=2.1Hz),8.00(d,1H,J=5.7Hz),7.13- 7.07(m,1H),6.34(d,1H,J=5.7Hz),5.89(brs,2H),3.93(s,2H),3.88(s,6H),2.69(t,2H,J= 6.6Hz),2.58(s,4H),2.56(s,2H),2.33(s,3H),1.62-1.47(m,4H);13C NMR(100MHz,CDCl3, ppm):δ159.4,158.5,156,8,155.8,149.5,149.2,147.7,143.8,142.4,133.6,133.4, 124.8,111.6,111.4,111.2,101.2,54.8,54.3,53.2,52.8,47.5,46.2,40.0,27.3,24.9; EI-MS:444(M)+;HRMS(EI):Calculated value：C22H30F2N8:444.2561;Measured value：444.2565.
The preparation flow of the fluoro- 2- pyridine carboxaldehydes of wherein 3,5- bis- is as follows：
In N2Under atmosphere, 2- cyano group -3,5- difluoro pyridine (350mg, 2.5mmol) is dissolved in tetrahydrofuran (THF) (30mL), is placed under the conditions of -20 DEG C, be added dropwise diisobutyl aluminium hydride (DIBAL-H) (1.0M) toluene solution (2.5mL, 2.5mmol) mixtures stir 4h under the conditions of -20 DEG C.Add methanol and reaction is quenched, add 1N HCl and adjust pH to 4-5. Reaction mixture is diluted with ethyl acetate, after washing twice, the drying of organic layer anhydrous sodium sulfate.Filtering and concentrating, residue column layer It is white solid (153mg, yield 44%) that analysis, which obtains the fluoro- 2- pyridine carboxaldehydes of 3,5- bis-,.
1H NMR(300MHz,CDCl3,ppm):δ10.13(s,1H),8.51(s,1H),7.35(t,1H,J=9.0Hz).
Embodiment 66
Compound 68：N1- ((3,5- dichloropyridine -2- bases) methyl)-N1- ((7- (4- methylpiperazine-1-yls) -3H- imidazoles [4,5-b] pyridine -2- bases) methyl) butane -1,4- diamines
Reaction process is identical with embodiment 38, and 3- methyl -2- is replaced with 3,5- dichloro-2-pyridyls formaldehyde only in step 7 Pyridine carboxaldehyde, it is white gum thing (yield 45%) to obtain title compound.
1H NMR(300MHz,CDCl3,ppm):δ8.45(s,1H),7.90(d,1H,J=6.0Hz),7.60(s,1H), 6.79(brs,2H),6.33(d,1H,J=6.0Hz),3.96(s,4H),3.88(s,4H),2.77(t,2H,J=6.0Hz),2,66 (t,2H,J=6.0Hz),2.58(s,4H),2.34(s,3H),1.63-1.56(m,4H);13C NMR(100MHz,CDCl3, ppm):δ153.8,153.5,147.6,146.1,145.9,136.5,136.4,131.0,130.2,124.7,101.2,56.3, 55.2,54.9,53.5,47.5,46.2,39.8,27.2,25.2;EI-MS:476(M)+;HRMS(EI):Calculated value： C22H30Cl2N8:476.1970;Measured value：476.1966.
The preparation flow of wherein 3,5- dichloro-2-pyridyls formaldehyde is as follows：
In N2Under atmosphere, 2- cyano group -3,5- dichloropyridine (432mg, 2.5mmol) is dissolved in THF (20mL), is placed in -20 Under the conditions of DEG C, toluene solution (2.5mL, 2.5mmol) mixtures that DIBAL-H (1.0M) is added dropwise stir under the conditions of -20 DEG C Mix 4h.Add methanol and reaction is quenched, add 1N HCl and adjust pH to 4-5.Reaction mixture is diluted with ethyl acetate, washing two After secondary, the drying of organic layer anhydrous sodium sulfate.Filtering and concentrating, it is yellow solid that residue column chromatography, which obtains title compound, (300mg, yield 70%).
1H NMR(300MHz,CDCl3,ppm):δ10.13(s,1H),9.05(s,1H),8.65(s,1H).
Embodiment 67
Compound 69：N1- (2- amino -6- chlorobenzyls)-N1- ((7- (4- methylpiperazine-1-yls) -3H- imidazoles [4,5-b] Pyridine -2- bases) methyl) butane -1,4- diamines
Step 1 is similar with to embodiment 38 to step 7, and 3- first is replaced with the chloro- 5- nitrobenzaldehydes of 2- only in step 7 Base -2- pyridine carboxaldehydes.
Step 8
By 2- (4- ((the chloro- 6- nitrobenzyls of 2-) ((7- (4- methylpiperazine-1-yls) -3H- imidazoles [4,5-b] pyridine -2- Base) methyl) amino) butyl) iso-indoles -1,3- diketone (31mg, 0.05mmol) is dissolved in 2mL EtOH, add Pd-C (6mg) and NH2-NH2.H2O (20 μ L, 0.35mmol), mixture is refluxed 4h, lets cool filtering, and filtrate concentration column chromatography obtains compound 69 be white gum thing (yield 50%).
1H NMR(300MHz,CDCl3,ppm):δ7.76(d,1H,J=4.8Hz),6.88-6.85(m,1H),6.67-6.65 (m,1H),6.45-6.42(m,1H),6.30(brs,1H),3.93-3.83(m,8H),2.82(brs,2H),2.58(brs, 4H),2.50(brs,2H),2.35(s,3H),1.66(brs,4H);EI-MS:456(M)+;HRMS(EI):Calculated value： C23H33ClN8:456.2517;Measured value：456.2524.
Embodiment 68
Compound 70：N1- (2,6- difluorobenzyls)-N1- ((7- (4- methylpiperazine-1-yls) -3H- imidazoles [4,5-b] pyrrole Pyridine -2- bases) methyl) butane -1,4- diamines
Reaction process is identical with embodiment 38, and 3- methyl -2- pyridine first is replaced with 2,6- difluorobenzaldehydes only in step 7 Aldehyde, it is white gum thing (yield 53%) to obtain title compound.
1H NMR(300MHz,CDCl3,ppm):δ7.77(d,1H,J=6.0Hz),7.26-7.15(m,1H),6.83(t, 2H,J=7.8Hz),6.30(d,1H,J=6.0Hz),3.97-3.91(m,4H),3.87(s,4H),2.96(t,2H,J=6.6Hz), 2.61(s,4H),2.44(t,2H,J=5.4Hz),2.36(s,3H),1.83-1.79(m,2H),1.72-1.68(m,2H);EI- MS:443(M)+;HRMS(EI):Calculated value：C23H31F2N7:443.2609;Measured value：443.2602.
Embodiment 69
Compound 71：N1- ((7- (4- methylpiperazine-1-yls) -3H- imidazoles [4,5-b] pyridine -2- bases) methyl)-N1-(5, 6,7,8- tetrahydroquinoline -8- bases) butane -1,4- diamines
Step 1 to step 6 with step 1 in embodiment 37 to step 6, only in step 6 with 6,7- dihydroquinoline -8 (5H) - Ketone replaces 3- methyl -2- pyridine carboxaldehydes.
Step 7：2- (4- (((7- (4- methylpiperazine-1-yls) -3H- imidazoles [4,5-b] pyridine -2- bases) methyl) (5,6, 7,8- tetrahydroquinoline -8- bases) amino) butyl) iso-indoles -1,3- diketone
By N- ((7- (4- methylpiperazine-1-yls) -3H- imidazoles [4,5-b] pyridine -2- bases) methyl) -5,6,7,8- tetrahydrochysenes Quinoline -8- amine (37mg, 0.1mmol) is dissolved in 2mL DCE, add 4- (1,3- dioxy iso-indoles -2- bases) butyraldehyde (26mg, 0.12mmol), NaBH (OAc) is added3(32mg, 0.15mmol), 12h is stirred at room temperature in mixture, is diluted with DCM, uses Saturated sodium bicarbonate is washed, and the drying of organic phase anhydrous sodium sulfate, filtering and concentrating, it is colourless that residue column chromatography, which obtains title compound, Jelly (43mg, yield 77%).
1H NMR(300MHz,CDCl3,ppm):δ 8.70 (d, 1H, J=3.9Hz), 8.03 (d, 1H, J=5.7Hz), 7.76- 7.75 (m, 2H), 7.67-7.66 (m, 2H), 7.38 (d, 1H, J=7.5Hz), 7.13-7.11 (m, 1H), 6.40 (d, 1H, J= 5.7Hz),4.03-3.95(m,7H),3.56-3.41(m,2H),2.87-2.54(m,8H),2.44(s,3H),2.17-1.83 (m,3H),1.68-1.38(m,5H).
Step 8:N1- ((7- (4- methylpiperazine-1-yls) -3H- imidazoles [4,5-b] pyridine -2- bases) methyl)-N1-(5,6, 7,8- tetrahydroquinoline -8- bases) butane -1,4- diamines
By 2- (4- (((7- (4- methylpiperazine-1-yls) -3H- imidazoles [4,5-b] pyridine -2- bases) methyl) (5,6,7,8- Tetrahydroquinoline -8- bases) amino) butyl) iso-indoles -1,3- diketone (43mg, 0.074mmol) is dissolved in 2mL absolute ethyl alcohols, add water Hydrazine (34 μ L, 0.594mmol) is closed, mixture is refluxed 2h, lets cool, and filtering, filtrate is spin-dried for column chromatography, and to obtain 27mg titled Compound is colorless gum (yield 80%).
1H NMR(300MHz,CDCl3,ppm):δ8.58(d,1H,J=4.2Hz),7.95(d,1H,J=5.7Hz),7.34 (d,1H,J=7.5Hz),7.07-7.01(m,1H),6.35(d,1H,J=5.7Hz),4.04-3.84(m,7H),2.85-2.49 (m,10H),2.32(s,3H),2.18-1.43(m,8H);13C NMR(100MHz,CD3OD,ppm):δ157.9,154.0, 149.0,147.9,147.8,145.2,139.2,136.8,123.6,123.5,103.9,63.5,55.7,46.2,40.5, 33.1,30.8,30.2,26.7,26.5,23.7,23.5,22.5;ESI-MS:449.2(M+1)+;HRMS(ESI):Calculated value： C25H37N8(M+H)+:449.3141;Measured value：449.3115.
The preparation flow of 4- (1,3- dioxy iso-indoles -2- bases) butyraldehyde wherein in step 7 is as follows：
Step 1：2- (4- brombutyls) iso-indoles -1,3- diketone
By phthalimide (1.176g, 7.98mmol), K2CO3(3.316g, 24mmol) and benzyl triethyl ammonium chlorination Ammonium (200mg, 0.88mmol) is dissolved in acetone (20mL), adds Isosorbide-5-Nitrae-dibromobutane (2.9mL, 24mmol) mixture at room temperature Stir 24h.Solvent is spin-dried for, residue is dissolved in water and DCM, isolates organic phase, and water layer is extracted twice with DCM again, merges organic Layer.Anhydrous sodium sulfate is dried, filtering and concentrating, and it is colourless solid that residue column chromatography, which obtains title compound 1.861g (yield 83%), Body.
1H NMR(300MHz,CDCl3,ppm):δ7.86-7.83(m,2H),7.73-7.70(m,2H),3.72(t,2H,J= 6.6Hz),3.44(t,2H,J=6.3Hz),1.93-1.82(m,4H).
Step 2：2- (4- hydroxybutyls) iso-indoles -1,3- diketone
2- (4- brombutyls) iso-indoles -1,3- diketone (564mg, 2mmol) is dissolved in H2O (1.5mL) and HMPA (8.5mL) Mixed liquor, mixture is refluxed 6h at 100 DEG C, cools down, is diluted with water, with ether extraction three times, merge organic phase without Aqueous sodium persulfate is dried, and it is colorless oil to be concentrated to give title compound 353mg (yield 81%), is directly used in next step.
Step 3：4- (1,3- dioxy iso-indoles -2- bases) butyraldehyde
2- (4- hydroxybutyls) iso-indoles -1,3- diketone (353mg, 1.61mmol) is dissolved in the anhydrous DCM of 10mL, N2Protection Under, DMP (1.026g, 2.42mmol) is added, 2h is stirred at room temperature in mixture, after being diluted with DCM, is washed with saturated sodium bicarbonate, Organic layer anhydrous sodium sulfate is dried, and it is white oil thing (yield 56%) that concentration column chromatography, which obtains 190mg title compounds,.
1H NMR(300MHz,CDCl3,ppm):δ9.75(s,1H),7.82-7.81(m,2H),7.72-7.69(m,2H), 3.72(t,2H,J=6.6Hz),2.52(t,2H,J=7.2Hz),2.04-1.95(m,2H).
Embodiment 70
Compound 72：N1- ((3- cyclopropyl pyridine -2- bases) methyl)-N1- ((7- (4- methylpiperazine-1-yls) -3H- imidazoles [4,5-b] pyridine -2- bases) methyl) butane -1,4- diamines
Reaction process is identical with embodiment 38, and 3- methyl -2- is replaced with 3- cyclopropyl -2- pyridine carboxaldehydes only in step 7 Pyridine carboxaldehyde, it is colorless gum (yield 45%) to obtain title compound.
1H NMR(300MHz,CDCl3,ppm):δ8.45(d,1H,J=4.5Hz),7.96(d,1H,J=6.0Hz),7.25 (d,1H,J=9.3Hz),7.11-7.07(m,1H),6.36(d,1H,J=6.0Hz),6.10(brs,2H),3.99(s,2H), 3.88-3.86(m,6H),2.71(t,2H,J=6.4Hz),2.64-2.58(m,6H),2.33(s,3H),2.14-2.05(m, 1H),1.64-1.58(m,2H),1.55-1.49(m,2H),0.94(d,2H,J=8.4Hz),0.62(d,2H,J=5.1Hz);13C NMR(100MHz,CD3OD,ppm):δ158.4,151.4,150.9,149.0,146.4,145.2,140.0,135.3,125.2, 124.1,103.7,58.5,55.7,55.2,53.2,46.2,40.7,27.5,24.9,12.6,8.0;EI-MS:448(M)+; HRMS(EI):Calculated value：C25H36N8:448.3063 measured value：448.3060.
The preparation flow of wherein 3- cyclopropyl -2- pyridine carboxaldehydes is as follows：
Step 1：3- cyclopropyl -2- picolines
N2Under atmosphere, to 3- bromine-2-methylpyridines (172mg, 1mmol), cyclopropylboronic acid (112mg, 1.3mmol), phosphorus In the toluene (4.0mL) and water of sour potassium (743mg, 3.5mmol) and thricyclohexyl phosphorus (28.0mg, 0.1mmol) (200 μ L) solution Add palladium (12.0mg, 0.05mmol).Mixture reacts 3h at 100 DEG C, lets cool to room temperature.Water (10mL) is added, with Ethyl acetate (2 × 15mL) extracts, and organic phase is washed after merging with saturated common salt, anhydrous sodium sulfate drying.Filtering and concentrating, it is remaining It is pale yellow oil (121mg, yield 91%) that thing column chromatography, which obtains title compound,.
1H NMR(300MHz,CDCl3,ppm):δ8.23-8.22(m,1H),7.17(d,1H,J=8.1Hz),6.97-6.93 (m,1H),2.58(s,3H),1.84-1.75(m,1H),0.93-0.86(m,2H),0.57-0.51(m,2H).
Step 2：3- cyclopropyl -2- pyridine carboxaldehydes
Selenium dioxide (106mg, 0.95mmol) and 3- cyclohexyl -2- picolines (121mg, 0.90mmol) are dissolved in two Six ring of oxygen (4mL), mixture is heated to reflux 17h.Let cool, filter, it is faint yellow that filtrate concentration column chromatography, which obtains title compound, Grease (55mg, yield 45%).
1H NMR(300MHz,CDCl3,ppm):δ10.28(s,1H),8.62-8.60(m,1H),7.40-7.33(m,2H), 3.14-3.05(m,1H),1.18-1.11(m,2H),0.77-0.72(m,2H).
Embodiment 71
Compound 73：N1- ((3-ethylpyridine -2- bases) methyl)-N1- ((7- (4- methylpiperazine-1-yls) -3H- imidazoles [4,5-b] pyridine -2- bases) methyl) butane -1,4- diamines
Reaction process is identical with embodiment 38, and 3- methyl -2- pyrroles are replaced with 3- ethyl -2- pyridine carboxaldehydes only in step 7 Pyridine formaldehyde, it is colorless gum (yield 62%) to obtain title compound.
1H NMR(300MHz,CDCl3,ppm):δ8.44(d,1H,J=4.2Hz),7.82(d,1H,J=5.4Hz),7.44 (d,1H,J=7.2Hz),7.11-7.07(m,1H),6.31(d,1H,J=6.3Hz),3.94-3.84(m,8H),3.00-2.98 (m,2H),2.72-2.59(m,8H),2.35(s,3H),1.77-1.72(m,4H),1.18(t,3H,J=7.5Hz);13C NMR (100MHz,CDCl3,ppm):δ155.2,150.9,149.2,147.4,146.1,141.0,138.0,136.8,124.2, 122.5,101.3,56.6,54.9,54.4,52.9,47.1,45.5,39.5,26.2,25.4,24.8,14.5;EI-MS:436 (M)+;HRMS(EI):Calculated value：C24H36N8:436.3063 measured value：436.3070.
The preparation flow of wherein 3- ethyls -2- pyridine carboxaldehydes is as follows：
Step 1：3- bromo-2-pyridyl formaldehyde
With step 1 in embodiment 50.
Step 2：3- ((trimethylsilyl) acetenyl) -2- pyridine carboxaldehydes
Load 3- bromo-2-pyridyls formaldehyde (558mg, 3mmol), bi triphenyl phosphorus palladium chloride into the reaction bulb of 50mL (105mg, 0.15mmol), cuprous iodide (29mg, 0.15mmol, 0.05eq), and DMF (3mL) add triethylamine (418 μ L, 3mmol) and after 1.5h is stirred at room temperature in trimethyl silicane ethyl-acetylene (768 μ L, 5.4mmol) mixtures, it is dilute with ethyl acetate Release.Organic layer uses water successively, after saturated common salt washing, is dried with anhydrous sodium sulfate.Filtering and concentrating, residue column chromatography are marked Topic compound is red oil (560mg, yield 93%).
1H NMR(300MHz,CDCl3,ppm):δ10.42(s,1H),8.73(d,1H,J=4.8Hz),7.92(d,1H,J= 7.8Hz),7.46-7.42(m,1H),0.295(s,9H).
Step 3：3- acetenyl -2- pyridine carboxaldehydes
3- ((trimethylsilyl) acetenyl) -2- pyridine carboxaldehydes (518mg, 2.55mmol) are dissolved in DMF (3mL), are added Dihydrate of potassium fluoride (480mg, 5.10mmol), mixture is in N2In room temperature reaction 3h under protection.It is poured into water, is extracted with dichloromethane Take, merge organic phase, anhydrous sodium sulfate drying, it is faint yellow solid that filtering and concentrating residue column chromatography, which obtains title compound, (247mg, yield 74%).
1H NMR(300MHz,CDCl3,ppm):δ10.26(s,1H),8.71(d,1H,J=4.5Hz),7.91(d,1H,J= 8.1Hz),7.46-7.42(m,1H),3.58(s,1H).
Step 4：3- ethyl -2- pyridine carboxaldehydes
3- acetenyl -2- pyridine carboxaldehydes (74mg, 0.56mmol) are dissolved in 5mL EtOAc, add Pd-C (8mg), mixing Thing is in H212h is stirred at room temperature under atmosphere, crosses and filters out Pd-C, it is light green oily that filtrate concentration column chromatography, which obtains title compound, Thing (40mg, yield 54%).
1H NMR(300MHz,CDCl3,ppm):δ10.14(s,1H),8.63-8.61(m,1H),7.63(d,1H,J= 7.5Hz),7.40-7.35(m,1H),3.05(q,2H,J=7.5Hz),1.20(t,3H,J=7.5Hz).
Embodiment 72
Compound 74：N1- ((7- (4- methylpiperazine-1-yls) -3H- imidazoles [4,5-b] pyridine -2- bases) methyl)-N1- ((3- vinylpyridine -2- bases) methyl) butane -1,4- diamines
Reaction process is similar to embodiment 38, and 3- methyl -2- pyrroles are replaced with 3- vinyl -2- pyridine carboxaldehydes in step 7 Pyridine formaldehyde, colorless gum is obtained when taking off phthalyl (pht) protection group in step 8 with ethylenediamine instead of hydrazine hydrate (yield 86%).
1H NMR(300MHz,CDCl3,ppm):δ8.47(d,1H,J=3.0Hz),7.80(d,1H,J=5.7Hz),7.65 (d,1H,J=7.8Hz),7.10-7.06(m,1H),6.98-6.89(m,1H),6.28(d,1H,J=6.3Hz),5.59(d,1H,J =17.7Hz),5.36(d,1H,J=11.1Hz),3.87-3.81(m,8H),3.00(t,2H,J=5.7Hz),2.59-2.57(m, 6H),2.34(s,3H),1.82-1.55(m,4H);13C NMR(100MHz,CDCl3,ppm):δ155.0,154.7,147.9, 147.7,134.0,133.0,132.6,132.4,122.9,122.6,118.4,118.0,101.0,57.2,54.9,54.8 (2C),53.2,47.6(2C),46.1,39.6,26.6,25.3;EI-MS:434(M)+;HRMS(EI):Calculated value：C24H24N8: 434.2906;Measured value：434.2900.
The preparation flow of wherein 3- vinyl -2- pyridine carboxaldehydes is as follows：
Step 1:3- bromo-2-pyridyl formaldehyde
It is identical with step 1 in embodiment 50.
Step 2:3- ((trimethylsilyl) acetenyl) -2- pyridine carboxaldehydes
It is identical with step 2 in embodiment 71.
Step 3:3- acetenyl -2- pyridine carboxaldehydes
It is identical with step 3 in embodiment 71.
Step 4:3- vinyl -2- pyridine carboxaldehydes
3- acetenyl -2- pyridine carboxaldehydes (74mg, 0.56mmol) are dissolved in 5mL EtOAc, add lindlar catalyst 2h is stirred at room temperature in (8mg), mixture in a hydrogen atmosphere, crosses and filters out catalyst, filtrate concentration residue column chromatography is marked It is colorless oil to inscribe compound (60mg, yield 81%).
1H NMR(300MHz,CDCl3,ppm):δ10.14(s,1H),8.65(d,1H,J=4.2Hz),7.93(d,1H,J= 8.1Hz),7.72-7.63(m,1H),7.45-7.40(m,1H),5.76(d,1H,J=17.7Hz),5.49(d,1H,J= 11.4Hz).
Embodiment 73
Compound 75：N1- ((3- isopropyl pyridine -2- bases) methyl)-N1- ((7- (4- methylpiperazine-1-yls) -3H- imidazoles [4,5-b] pyridine -2- bases) methyl) butane -1,4- diamines
Reaction process is identical with embodiment 38, and 3- methyl -2- is replaced with 3- isopropyl -2- pyridine carboxaldehydes only in step 7 Pyridine carboxaldehyde, it is colorless gum (yield 68%) to obtain title compound.
1H NMR(300MHz,CDCl3,ppm):δ8.45(d,1H,J=3.9Hz),7.83(d,1H,J=5.4Hz),7.54 (d,1H,J=7.5Hz),7.15-7.11(m,1H),6.33(d,1H,J=6.0Hz),3.98(brs,4H),3.88(brs,4H), 3.21-3.14(m,1H),3.08(brs,2H),2.83-2.77(m,4H),2.59(brs,2H),2.49(s,3H),1.84- 1.72(m,4H),1.16(d,6H,J=6.3Hz);13C NMR(100MHz,CD3OD,ppm):δ155.8,151.3,150.8, 148.5,146.8,145.4,145.1,135.9,124.7,124.6,103.8,57.9,55.1,54.9,52.6,47.8, 45.1,40.4,29.0,26.6,24.8,23.7;EI-MS:450(M)+;HRMS(EI):Calculated value：C25H38N8:450.3219; Measured value：450.3213.
The preparation flow of wherein 3- isopropyls -2- pyridine carboxaldehydes is as follows：
Step 1：Isopropyl alkene boric acid
Trimethylborate (4.088mL, 36mmol) is dissolved in the THF of 5mL dryings, is placed in -78 DEG C of reactors, then be added dropwise to The isopropyl alkene magnesium bromide THF solution (30mL, 15mmol) of 0.5M.Drop finishes, and obtained white slurry thing is warmed to room temperature naturally, reaction Overnight.Add 5mL water quenchings to go out reaction, be spin-dried for THF, residue is placed in 0 DEG C, addition 2N HCl (15mL), and stir 30min, Then with ether extraction three times, combined ether extraction liquid, anhydrous sodium sulfate drying, filtering and concentrating obtains title compound, and (567mg, is received Rate 44%) it is white solid.It is placed in N2The lower storage of protection.
1H NMR(300MHz,CD3OD,ppm):δ5.53-5.46(m,2H),1.72(s,3H).
Step 2：2- methyl -3- isopropenyl pyridines
By 3- bromine-2-methylpyridines (880mg, 5.12mmol), isopropyl alkene boric acid (661mg, 7.69mmol) and potassium carbonate (3.64g, 26.32mmol) is dissolved in the mixed liquor of DME (46mL) and water (5.12mL), and reaction bulb, which vacuumizes, changes N2After three times, in N2 Under protection, Pd (dppf) is added2Cl2.CH2Cl2(460mg, 0.56mmol).Mixture reacts 2h under the conditions of 90 DEG C, cooling Afterwards, with ether extraction three times, combined ether extraction liquid, anhydrous sodium sulfate drying, filtering and concentrating, residue column chromatography obtain title compound Thing is brown oil (444mg, yield 65%).
1H NMR(300MHz,CDCl3,ppm):δ8.41(d,1H,J=4.5Hz),7.45(d,1H,J=7.5Hz),7.15- 7.11(m,1H),5.26(s,1H),4.91(s,1H),2.58(s,3H),2.04(s,3H).
Step 3：2- methyl -3- isopropyl pyridines
2- methyl -3- isopropenyl pyridines (463mg, 3.48mmol) are dissolved in 10mL EtOAc, add Pd-C (46mg), Mixture in room temperature reaction 12h, is crossed in a hydrogen atmosphere and filters out Pd-C, and filtrate concentration, residue is pale yellow oil (363mg, yield 78%), is directly used in next step.
1H NMR(300MHz,CDCl3,ppm):8.59(d,1H,J=4.5Hz),7.79(d,1H,J=7.8Hz),7.42- 7.38(m,1H),4.15-4.06(m,1H),2.53(s,3H),1.21-1.18(m,6H).
Step 4：3- isopropyl -2- pyridine carboxaldehydes
By SeO2(119mg, 1.08mmol) and 2- methyl -3- isopropyl pyridines (121mg, 0.89mmol) are dissolved in dioxy six Ring (4mL), mixture are stirred at reflux 12h, and cold filtration, it is pale yellow oil that filtrate concentration column chromatography, which obtains title compound, (38mg, yield 30%).
1H NMR(300MHz,CDCl3,ppm):δ10.14(s,1H),8.59(d,1H,J=4.5Hz),7.79(d,1H,J= 7.8Hz),7.42-7.38(m,1H),4.15-4.06(m,1H),1.21-1.18(m,6H).
Embodiment 74
Compound 76：N1- ((7- (4- methylpiperazine-1-yls) -3H- imidazoles [4,5-b] pyridine -2- bases) methyl)-N1- (pyrrole Pyridine -3- ylmethyls) butane -1,4- diamines
Reaction process is identical with embodiment 38, and 3- methyl -2- pyridine carboxaldehydes are replaced with 3- pyridine carboxaldehydes only in step 7, It is colorless gum (yield 85%) to obtain title compound.
1H NMR(300MHz,CDCl3,ppm):δ8.57(s,1H),8.39(d,1H,J=4.2Hz),7.90(d,1H,J= 5.7Hz),7.68(d,1H,J=8.1Hz),7.13-7.09(m,1H),6.34(d,1H,J=5.7Hz),6.00(brs,2H), 3.91(brs,4H),3.84(s,2H),3.65(s,2H),2.72(brs,2H),2.58(brs,4H),2.49(brs,2H), 2.33(s,3H),1.57(brs,4H);13C NMR(100MHz,CDCl3,ppm):δ150.2,149.7,148.7,148.4, 147.6,143.7,136.8,134.0,124.7,123.2,101.6,55.9,54.8(2C),53.3,52.1,47.6(2C), 46.2,40.7,29.0,23.9;EI-MS:408(M)+;HRMS(EI):Calculated value：C22H32N8:408.2750;Measured value： 408.2743.
Embodiment 75
Compound 76：1- (3- cyclopropyl pyridine -2- bases)-N- methyl-N- ((7- (4- methylpiperazine-1-yls) -3H- imidazoles [4,5-b] pyridine -2- bases) methyl) methylamine
Reaction process is identical with embodiment 37, and 3- methyl -2- is replaced with 3- cyclopropyl -2- pyridine carboxaldehydes only in step 6 Pyridine carboxaldehyde, it is colorless gum (yield 50%) to obtain compound 76.
Wherein the preparation of 3- cyclopropyl -2- pyridine carboxaldehydes is the same as embodiment 70.
1H NMR(300MHz,CDCl3,ppm):δ8.47(dd,1H,J1=4.6Hz,J2=1.2Hz),8.01(d,1H,J= 6.0Hz),7.26(d,1H,J=6.9Hz),7.16-7.11(m,1H),6.39(d,1H,J=6.0Hz),3.99(t,4H,J= 4.5Hz),3.95(s,2H),3.88(s,2H),2.74(t,4H,J=4.8Hz),2.44(s,6H),2.20-2.11(m,1H), 0.98-0.92(m,2H),0.65-0.60(m,2H);13C NMR(100MHz,CDCl3,ppm):δ156.9,149.2,148.8, 147.2,145.8,143.3,138.1,133.7,124.8,122.6,101.9,59.0,54.4,54.3,46.9,45.3, 43.3,11.7,7.6;EI-MS:391(M+);HRMS(EI):Calculated value：C22H29N7:391.2484;Measured value：391.2485.
Embodiment 76
Compound 78：(E) -3- (2- (((4- aminobutyls) ((7- (4- methylpiperazine-1-yls) -3H- imidazoles [4,5-b] Pyridine -2- bases) methyl) amino) methyl) pyridin-3-yl) acrylonitrile
Reaction process is similar to embodiment 38, and 3- first is replaced with (E) -3- (2- formoxyl -3- bases) acrylonitrile in step 7 Base -2- pyridine carboxaldehydes, title compound is obtained as colorless gum when step 8 takes off pht protection groups using ethylenediamine instead of hydrazine hydrate Thing (yield 41%).
1H NMR(300MHz,CDCl3,ppm):δ8.59(d,1H,J=3.9Hz),7.79(d,1H,J=5.7Hz),7.61- 7.56(m,2H),7.15-7.11(m,1H),6.31(d,1H,J=5.7Hz),5.81(d,1H,J=16.5Hz),3.94-3.81 (m,8H),3.06(brs,2H),2.67-2.59(m,6H),2.40(s,3H),1.80-1.58(m,4H);EI-MS:459(M)+; HRMS(EI):Calculated value：C25H33N9:459.2859;Measured value：459.2858.
The preparation flow of wherein (E) -3- (2- formoxyl -3- bases) acrylonitrile is as follows：
Step 1：3- (2- picoline -3- bases) acrylonitrile
By 3- bromine-2-methylpyridines (1.72g, 10mmol), acrylonitrile (3.29mL, 50mmol), Pd (OAc)2(244mg, 1mmol),n-Bu4NCl (2.78g, 10mmol) and NaHCO3(4.2g, 50mmol) is dissolved in 15mL DMF.Mixture is in N2Protection Under be placed under the conditions of 110 DEG C of microwave and react 5h.After cooling, DMF is spin-dried for, residue is with water and DCM liquid separations, organic phase anhydrous slufuric acid Sodium is dried, and filtering and concentrating, it is white gum thing (1.33g, yield 93%) that residue column chromatography, which obtains title compound,.
1H NMR(300MHz,CDCl3,ppm):δ8.52-8.50(m,1.5H),8.18(d,0.5H,J=7.8Hz),7.72 (d,1H,J=7.8Hz),7.63(d,1H,J=16.5Hz),7.37(d,0.5H,J=11.7Hz),7.26-7.24(m,0.5H), 7.21-7.18(m,1H),5.83(d,1H,J=16.5Hz),5.64(d,0.5H,J=11.7Hz),2.62(s,3H),2.58(s, 1.5H).
Step 2：(E) -3- (2- formylpyridine -3- bases) acrylonitrile
By SeO2(1.24g, 11.12mmol) and 3- (2- picoline -3- bases) acrylonitrile (1.34g, 9.31mmol) is molten In dioxane (16mL), mixture is refluxed 16h, cold filtration, and filtrate concentrates, and residue column chromatography obtains title compound Thing is brown solid (270mg, yield 20%).
1H NMR(300MHz,CDCl3,ppm):δ10.16(s,1H),8.86(d,1H,J=4.2Hz),8.46(d,1H,J= 16.5Hz),7.93(d,1H,J=8.1Hz),7.60-7.56(m,1H),5.92(d,1H,J=16.5Hz).
Embodiment 77
Compound 79：1- (3-ethylpyridine -2- bases)-N- methyl-N- ((7- (4- methylpiperazine-1-yls) -3H- imidazoles [4,5-b] pyridine -2- bases) methyl) methylamine
Reaction process is identical with embodiment 37, and 3- methyl -2- pyrroles are replaced with 3- ethyl -2- pyridine carboxaldehydes only in step 6 Pyridine formaldehyde, it is colorless gum (yield 32%) to obtain title compound.
1H NMR(300MHz,CD3OD,ppm):δ8.48(d,1H,J=4.8Hz),8.00(d,1H,J=6.3Hz),7.77 (d,1H,J=7.5Hz),7.42-7.38(m,1H),6.70(d,1H,J=6.3Hz),4.30(brs,6H),3.37(brs,4H), 2.91(s,3H),2.75-2.67(m,7H),1.20(t,3H,J=7.2Hz);13C NMR(100MHz,CDCl3,ppm):δ 155.9,151.1,148.9,147.1,140.7,139.9,138.2,128.4,126.8,125.5,103.7,59.6,56.5, 54.9(2C),47.0(2C),44.4,43.6,25.6,15.0;EI-MS:379(M+);HRMS(EI):Calculated value：C21H29N7(M )+:379.2484;Measured value：379.2485.
Wherein the preparation of 3- ethyls -2- pyridine carboxaldehydes is the same as embodiment 71.
Embodiment 78
Compound 80：N1- ((1H- benzimidazolyl-2 radicals-yl) methyl)-N1- (5,6,7,8- imidazolidines [1,2-a] pyridine- 8- yls) butane -1,4- diamines
Step a：3- (benzyloxy) pyridine -2- amine
By 2- amino -3- pyridones (11g, 100mmol), benzyl chloride (12.66mL, 110mmol) and tetrabutylammonium bromide (3g, 10mmol) is dissolved in the sodium hydroxide solution and 50mL dichloromethane of 50mL40%, and 19h is stirred at room temperature in mixture.Instead After answering, liquid separation, water is extracted three times after mutually being diluted with water with dichloromethane, merges organic phase, anhydrous sodium sulfate drying, is filtered Concentration, it is brown solid (12g, yield 60%) that residue column chromatography, which obtains title compound,.
1H-NMR(CDCl3):δ7.68(dd,1H,J1=3.6Hz,J2=1.2Hz),7.44-7.32(m,5H),6.96(dd, 1H,J1=6.0Hz,J2=0.6Hz),6.59(dd,1H,J1=6.0Hz,J2=3.9Hz),5.07(s,2H),4.72(brs,2H).
Step b：8- (benzyloxy) imidazoles [1,2-a] pyridine
Sodium acid carbonate is added into the ethanol solution (60mL) of 3- (benzyloxy) pyridine -2- amine (11.88g, 59.4mmol) (9.98g, 118.8mmol) and chloroacetaldehyde (10.7mL, 162.2mmol), mixture are refluxed reaction 16h.Let cool, filter, Gained residue is diluted with dichloromethane after filtrate concentration, adds the sodium hydroxide solution tune PH to 10 of 30mL40%.Liquid separation, water Three times, merging organic phase, anhydrous sodium sulfate drying after Xiang Yishui dilutions with dichloromethane extraction, filtering and concentrating, column chromatography obtains It is faint yellow solid (8.29g, yield 64%) to title compound.
1H-NMR(CDCl3):δ7.76(d,1H,J=6.9Hz),7.57(d,2H,J=12.6Hz),7.50(d,2H,J= 7.2Hz),7.39-7.26(m,3H),6.62(t,1H,J=7.2Hz),6.46(d,1H,J=7.2Hz),5.33(s,2H).
Step c：5,6,7,8- imidazolidines [1,2-a] pyridine -8- alcohol
8- (benzyloxy) imidazoles [1,2-a] pyridine (5.9g, 0.025mol) and 202mg palladium carbons are dissolved in 50mL ethanol, mixed 7h is stirred at room temperature under 50psi nitrogen atmospheres in compound.Cross and filter out catalyst, it is faint yellow that filtrate column chromatography, which obtains title compound, Solid.
1H-NMR(CDCl3):δ8.68(brs,1H),7.42(s,1H),7.18(s,1H),5.39(t,1H,J=4.8Hz), 4.46-4.38(m,1H),4.32-4.24(m,1H),2.79-2.66(m,1H),2.53-2.48(m,2H),2.36-2.29(m, 1H).
Step d：6,7- glyoxalidine [1,2-a] pyridine -8 (5H) -one
5,6,7,8- imidazolidine [1,2-a] pyridine -8- alcohol (1.638g, 12.32mmol) are dissolved in 20mL dichloromethane, Dess-Martin oxidants (6.27g, 14.78mmol) are added, 2h is stirred at room temperature in mixture, after completion of the reaction, adds full And sodium bicarbonate solution, liquid separation, water are mutually extracted twice again with dichloromethane, merge organic phase, anhydrous sodium sulfate drying, is filtered dense Contracting, residue column chromatography obtain title compound as yellow solid (650mg, yield 41%).
1H-NMR(CDCl3):δ7.23(s,1H),7.02(s,1H),4.20(t,2H,J=6.0Hz),2.65(t,2H,J= 6.6Hz),2.34-2.26(m,2H).
Step e：4- (5,6,7,8- imidazolidines [1,2-a] pyridine -8- bases amino) butylcarbamate
Under stirring, to 6,7- glyoxalidine [1,2-a] pyridine -8 (5H) -one (68mg, 0.5mmol) and single carbon tert-butyl acrylate Sodium triacetoxy borohydride is added in 1,2- dichloroethanes (5mL) solution of protection butylamine (141mg, 0.75mmol) (211mg, 1mmol) and acetic acid (29 μ L, 0.5mmol).Mixture is stirred at room temperature overnight, and reaction finishes, and concentrates direct column It is white oil thing (125mg, yield 81%) that chromatography, which obtains title compound,.
1H-NMR(CDCl3):δ7.00(s,1H),6.79(s,1H),4.94(brs,1H),3.95(brs,3H),3.12 (brs,2H),2.90-2.67(m,3H),2.30-1.58(m,8H),1.43(s,9H).
Step f：2- (((4- (t-butyloxycarbonyl amino) butyl) (5,6,7,8- imidazolidines [1,2-a] pyridine -8- Base) amino) methyl) -1H- benzimidazole -1- carboxylic acid tert-butyl esters
Under stirring, to 2- (chloromethyl) -1H- benzimidazole -1- carboxylic acid tert-butyl esters (130mg, 0.49mmol) and 4- (5,6, 7,8- imidazolidines [1,2-a] pyridine -8- bases amino) butylcarbamate (125mg, 0.41mmol) acetonitrile N,N-diisopropylethylamine (100 μ L, 0.61mmol) and potassium iodide (7mg, 0.041mmol) are sequentially added in (5mL) solution.It is mixed Compound stirred at 60 DEG C reaction 12h, solvent evaporated, residue column chromatography obtain title compound for colorless gum (53mg, Yield 50%).
1H-NMR(CDCl3):δ7.86-7.83(m,1H),7.73-7.70(m,1H),7.31-7.28(m,2H),7.11(s, 1H),6.97(s,1H),4.88(brs,1H),4.61-4.41(m,2H),4.37-4.32(m,1H),4.10-3.93(m,2H), 3.02-2.70(m,4H),2.24-2.16(m,2H),2.05-1.90(m,2H),1.68(s,9H),1.56-1.42(m,4H), 1.39(s,9H).
Step g：N1- ((1H- benzimidazolyl-2 radicals-yl) methyl)-N1- (5,6,7,8- imidazolidines [1,2-a] pyridine -8- Base) butane -1,4- diamines
Under 0 DEG C of stirring, to 2- (((4- (t-butyloxycarbonyl amino) butyl) (5,6,7,8- imidazolidines [1,2-a] Pyridine -8- bases) amino) methyl) and -1H- benzimidazole -1- carboxylic acid tert-butyl esters (53mg, 0.098mmol) ethyl acetate (2mL) 6NHCl (1mL) is added in solution.4h is stirred at room temperature in mixture, is neutralized with saturated sodium carbonate solution, liquid separation, organic phase without Aqueous sodium persulfate is dried, and filtering and concentrating, it is white gum thing (27mg, yield 82%) that residue column chromatography, which obtains title compound,.
1H-NMR(CDCl3):δ7.59-7.56(m,2H),7.17-7.15(m,2H),7.05(s,1H),6.80(s,1H), 5.69(brs,2H),4.09-3.85(m,5H),3.50(s,1H),2.63-2.55(m,4H),2.24-2.19(m,2H),1.91- 1.73(m,2H),1.42(brs,4H);EI-MS:339(M+H)+.
The test of testing example biological activity
Test case 1
Suppress HIV integrase activity test：
AlphaScreen integrates Enzyme assay and is carried out in Optiplate-384 microwell plates.By the whole of histidine mark The testing compound of synthase (300nM) and various concentrations (0.1 μM, 1 μM, 10 μM, 100 μM) is in reaction buffer (25mM Tris (trishydroxymethylaminomethane)-HCl pH7.4,150mM NaCl, 1mM MgCl2, 0.01% Tween-20 and 0.1% ox blood are pure Albumen) in 4 DEG C incubation 30min.Adding the LEDGF/p75 (100nM) for being marked with Flag labels, that 1 is incubated under the conditions of 4 DEG C is small When.The donor bead that the acceptor bead and 5 μ L that then 5 μ L nickel of addition chelating wraps up are associated with Flag antibody causes its final concentration of 20 μ g/ ML, and by microwell plate when incubation 1 is small under the conditions of 30 DEG C so that albumen is full cross-linked with pearl.With Multilabel Reader read signal under AlphaScreen patterns and (are excited with 680nm, in 615nm detection fluorescence letters Number).
LEDGF/p75 is confactor main in hiv integrase core, and the combination for suppressing itself and hiv integrase is exploitation Suppress the important means of HIV medicines.This test case is by the method detection compound of AlphaScreen to integrase and LEDGF/ The influence that p75 is combined, carrys out inhibitory action of the detection compound to hiv integrase.
AlphaScreen is the side that two intermolecular interactions are detected by fluorescence energy transfer (TRF-FRAT) Method.The acceptor bead of nickel chelating parcel can be combined with histone label, and being associated with the donor bead of Flag antibody can be combined with Flag labels, When LEDGF/p75 is combined with hiv integrase, donor bead and acceptor pearl will be made close, when laser irradiates, will be occurred The excitation acceptor of energy transfer, i.e. donor sends fluorescence, by detecting the fluorescence of acceptor emission with regard to that can detect LEDGF/ P75 is combined with hiv integrase.
Suppress the active testing of hiv integrase dimerization：
The test of integrase dimerization activity usesMethod, in OptiWell384- holes, microwell plate (is purchased from Perkin Elmer companies) on carry out, be 25 μ L per hole final volume.The mother liquor of inhibitor and integrase is in assay buffer (150mM NaCl, 25mM Tris-HCl pH7.3,1mM MgCl2, 1mM DTT (dithiothreitol (DTT)), 0.1% (v/v) tween- 20 and 0.1% (w/v) 0.1% bovine serum albumin(BSA)) in be all diluted 5 times.First, 5 μ L inhibitor are added to 384 orifice plates with liquid-transfering gun Micropore in, then add the integrase of 5 μ LGST- marks and the integrase mother liquor of 5 μ L 6xHis- marks, microwell plate is enclosed within When 4 DEG C of hatchings 3 are small, dimerisation process is allowed to reach balance.Then, the donor magnetic bead and Ni of 10 μ L glutathione parcel are added2+Bag The receptor magnetic bead mixed liquor (being purchased from Perkin Elmer companies) wrapped up in.In this way, the final volume of each micropore is 25 μ L, each magnetic The final concentration of 10 μ g/mL of pearl, the concentration of each integrase protein is 30nM.Then, it is small to hatch 2 again at room temperature for microwell plate When, useMultilabel Reader (being purchased from Perkin-Elmer companies) are read under AlphaScreen patterns Signal (is excited, fluorescence signal is detected in 615nm) with 680nm.It is crosslinked that the compound of suppression integrase dimerization will change magnetic bead Degree and the output signal to accompany.Inhibitory activity phase of the degree (being represented with inhibiting rate %) that signal weakens directly with small molecule Close.
Test of the mtt assay to HCT116p53+ /+cytotoxicity：
Cytotoxicity test is MTT (3- (4,5- dimethylthiazole -2- bases) -2,5- diphenyltetrazolium bromide bromide) Method.HCT116p53+ /+cell inoculation in 96 orifice plates and is allowed into its attachment overnight.Then add corresponding testing compound and allow When their continuous actions 72 are small.Then, MTT solution (final concentration 0.5mg/mL) is added into each orifice plate and small in 37 DEG C of hatchings 4 When.After removing supernatant, dimethyl sulfoxide is added, reads the light absorption value of 570 nanometers.CC50Value is killed carefully with testing compound The percentage of born of the same parents and the logarithmic plot of testing compound concentration come definite.
Molecular level suppresses the protein-protein interaction activity between hiv integrase and LEDGF/p75, suppresses HIV and integrates Enzyme dimerization activity and toxicity to HCT116p53+ /+cell are listed in the table below 1：
Table 1
"-" represents not measure in table.
Test case 2
Cellular level anti HIV-1 virus active testing：
The present invention also have chosen part of compounds and carry out cellular level anti HIV-1 virus active testing.
First, medicine and compound are measured
Positive reference compound retrovir (3 '-Azido-3 ' deoxythymidine, AZT) is purchased from Sigma companies.
Testing compound is dissolved in DMSO, and storage liquid concentration is 2.5mg/mL, and condition of storage is：4℃.
AZT is dissolved in RPMI-1640 complete mediums, and 0.22 μm of membrane filtration is degerming, -20 DEG C of preservations after packing.
2nd, reagent and solution
(1) reagent
HEPES (4- hydroxyethyl piperazineethanesulfonic acids), MTT ((four nitrogen of 3- (4,5- dimethylthiazole -2- bases) -2,5- diphenyl Azoles bromide)), DMF (N, N '-dimethyl formamide), penicillin (Penicillin), streptomycin sulphate (Streptomycin Sulfate), glutamine (Glutamine) is purchased from Sigma companies；2 mercapto ethanol (2-ME, 2- Mercaptoethanol) it is Bio-Rad Products.RPMI-1640 and hyclone are Gibco Products.
(2) culture medium
RPMI-1640 complete mediums, contain 10% hyclone, 2mM L-Glutamines, 10mM HEPES, 50 μM of 2- Mercaptoethanol, 100,000IU penicillin, 100 μ g/mL streptomysins.
3rd, cell and virus
Human T lymphocyte system C8166, HIV-1 test strain HIV-1IIIB by Britain Medical Research Council, AIDS Reagent Project give.All cells and virus are with the RPMI-1640 containing 10% hyclone Complete medium is cultivated.HIV-1 IIIB are prepared according to a conventional method, are titrated and are calculated the TCID50 of virus.Virus storage After liquid packing, -70 DEG C of preservations are put.Cell and virus freeze and recover according to a conventional method.
4th, HIV-1 infectious titrations
HIV-1 IIIB are titrated by the improvement of Johnson ＆ Byington (1990) the method, are summarized as follows：Will HIV-1 storage liquid makees 4 times of dilutions on 96 orifice plates, and 10 gradients, per 6 repeating holes of gradient, while set 6 hole of control wells.Often Hole adds 50 μ L of C8166 cells, is 200 μ L per hole final volume.37 DEG C, 5%CO2Culture.It is complete to add fresh RPMI-1640 within 3rd day Full culture medium 100 μ L, the cytopathic effect (Cytopathic that HIV-1 is induced in being observed under inverted microscope per hole for the 7th day Effect, CPE), the formation for whether having plasomidum (Syncytium) with every hole determines；Disease is calculated by Reed ＆ Muench methods The TCID50 (50%Tissue Culture Infection Dose) of poison.
5th, to the Inhibition test of HIV-1 IIIB cytopathogenic effects (CPE)
By 8 × 10550 μ L/ holes of/mL C8166 cells are inoculated into 96 holes containing 100 μ L/ gradient pores doubling dilution medicines On Tissue Culture Plate, the HIV-1IIIB dilution supernatants of 50 μ L, 1300TCID50/ holes are then added.If 3 repeating holes.Set at the same time Put the normal cell controls hole of not drug containing.AZT is positive drug control.37 DEG C, 5%CO2Culture 3 days, under inverted microscope (100 ×) formation of plasomidum is counted.EC50(50%Effective Concentration) is suppression Syncytium formation 50% When drug concentration.The results are shown in table 2 below：
Table 2
As can be seen from Table 1, majority of compounds of the invention is to albumen-egg between hiv integrase and LEDGF/p75 White interaction and the IC to hiv integrase dimerization50It is all horizontal in micromolar levels or 100nM, and these compounds are basic No cytotoxicity.The part the compounds of this invention chosen as can be seen from Table 2 all has cellular level anti HIV-1 virus activity, The anti-HIV-1 EC of compound 4050Reach 0.005 μ g/mL.Therefore, the compounds of this invention is good hiv integrase and LEDGF/ The inhibitor of protein-protein interaction between p75 and the inhibitor of hiv integrase dimerization, also show that good in vitro AIDS virus resisting effect, available for treating AIDS.
Only illustratively, the scope of the present invention is not limited thereto for above-mentioned example.To those skilled in the art For modify be it will be apparent that the present invention only limited by scope.

Claims (7)

1. polysubstituted aminated compounds or its pharmaceutically acceptable salt shown in the following general formula II-a：
Wherein, K1Selected from following atom or group：Hydrogen, C1-C6Alkyl, halogen, cyano group C1-C6Alkylidene ,-(CH2)o-C(O)- OH、-(CH2)o-C(O)-OR7、-(CH2)o-C(O)-NR5R6、-(CH2)o-NR7R8、-(CH2)o-NHC(O)R9With-(CH2)o-NHS (O)2R10, wherein o be 1-6 integer, R5For hydrogen, R6For hydrogen, C1-C6Alkyl, C3-C8Cycloalkyl or it is unsubstituted or by selected from C1-C6Alkyl, halogen, amino, NO2, sulfydryl, hydroxyl, CN and CF3In the benzyl that is substituted of 1-3 substituent, R7And R8But that This is identical or different, and is each independently hydrogen or C1-C6Alkyl, R9For C1-C6It is alkyl, unsubstituted or by selected from C1-C6 Alkyl, halogen, amino, NO2, sulfydryl, hydroxyl, CN and CF3In 1-3 the substituent benzyl, the C that are substituted1-C6Alkoxy carbonyl Base or C1-C6Alkylaminocarbonyl, R10For C1-C6Alkyl；And
K4Selected from following atom or group：Hydrogen and C1-C6Alkoxy carbonyl.
2. polysubstituted aminated compounds according to claim 1 or its pharmaceutically acceptable salt, wherein, general formula II-a institutes The compound shown is the compound shown in the following general formula II-a1 to II-a2：
Wherein K1Definition with its definition in general formula II-a.
3. a kind of polysubstituted aminated compounds or its pharmaceutically acceptable salt, it is selected from following compounds：
4. polysubstituted aminated compounds according to any one of claims 1 to 3 or its pharmaceutically acceptable salt are preparing use Purposes in the medicine for the treatment of AIDS.
5. a kind of be used to treat the pharmaceutical composition of AIDS, it includes therapeutically effective amount in claims 1 to 3 it is any Polysubstituted aminated compounds or its pharmaceutically acceptable salt described in, and optionally further include pharmaceutically acceptable Carrier.
6. the inhibitor of the protein-protein interaction and hiv integrase dimerization between a kind of hiv integrase and LEDGF/p75, It includes therapeutically effective amount selected from polysubstituted aminated compounds according to any one of claims 1 to 3 or its pharmaceutically may be used The salt of receiving, and optionally further include pharmaceutically acceptable carrier.
7. polysubstituted aminated compounds according to any one of claims 1 to 3 or its pharmaceutically acceptable salt are used to prepare The purposes of the inhibitor of protein-protein interaction and hiv integrase dimerization between hiv integrase and LEDGF/p75.
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